Hello Tom,
Thank you for a very interesting question. In a Medline search, I
found nearly 30 conditions in which neurotrophic substances have
potential therapeutic application. Unless otherwise stated, the URLs
are to the author abstract of the article on Medline. I have listed
only the most recent articles for each of the conditions.
A fairly recent general review:
Nature Neurosci 2002 Nov;5 Suppl:1046-50
Neurotrophins: from enthusiastic expectations through sobering
experiences to rational therapeutic approaches.
Thoenen H, Sendtner M.
Max Planck Institute of Neurobiology, Am Klopferspitz 18a, 82152
Martinsried-Munchen, Germany.
“Despite high enthusiasm, early attempts to develop clinical
treatments based on animal research with neurotrophins were not
successful. Here we survey clinical trials with neurotrophins,
compared with neurotrophic factors of other gene families, and
delineate the most likely reasons for their failure. We then suggest
improved methods for regulated local supply of NTs to specific
populations of neurons and discuss future therapeutic procedures
evolving from the more detailed knowledge of the signal transduction
pathways activated by neurotrophins via their receptors.”
Full text at:
http://www.nature.com/cgi-taf/DynaPage.taf?file=/neuro/journal/v5/n11s/full/nn938.html
1.Obesity and diabetes
a) Int J Obes Relat Metab Disord 2003 May;27(5):557-65
Anti-obesity and anti-diabetic effects of brain-derived neurotrophic
factor in rodent models of leptin resistance.
Nakagawa T, Ogawa Y, Ebihara K, Yamanaka M, Tsuchida A, Taiji M,
Noguchi H, Nakao K.
Discovery Research Laboatories I, Sumitomo Pharmaceuticals Research
Division, Osaka, Japan.
“In this study, we investigated whether or not BDNF is effective in
two different models of leptin resistance, an acquired model and a
genetic model. DESIGN: C57BL/6J mice rendered obese by consumption of
a high-fat diet (diet-induced obesity (DIO) mice) were used as an
acquired model and lethal yellow agouti mice (KKA(y) mice) as a
genetic model of leptin resistance….
This study demonstrated antiobesity and antidiabetic effects of BDNF
in two different models of leptin resistance, thereby suggesting the
therapeutic potential of BDNF in the treatment of leptin-resistant
obesity and diabetes.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12704399&dopt=Abstract
b) Diabetes Obes Metab 2002 Jul;4(4):262-9
Brain-derived neurotrophic factor ameliorates lipid metabolism in
diabetic mice.
Tsuchida A, Nonomura T, Nakagawa T, Itakura Y, Ono-Kishino M, Yamanaka
M, Sugaru E, Taiji M, Noguchi H.
Sumitomo Pharmaceuticals Co. Ltd, Discovery Research Laboratories II,
Konohana-ku, Osaka 554-0022, Japan.
“It has been reported previously that brain-derived neurotrophic
factor (BDNF) regulates blood glucose metabolism in rodent obese
diabetic models such as C57BL/KsJ-leprdb/leprdb (db/db) mice. BDNF
further regulates energy expenditure, possibly through the central and
autonomous nervous systems…. Taken together with the accelerating
effect of BDNF on energy metabolism, these findings indicate that BDNF
improves glucose and lipid metabolism in obese diabetic animals
without enlarging liver or adipose tissues.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12099975&dopt=Abstract
c) Metabolism 2003 Feb;52(2):203-8
Brain-derived neurotrophic factor ameliorates hepatic insulin
resistance in Zucker fatty rats.
Kuroda A, Yamasaki Y, Matsuhisa M, Kubota M, Nakahara I, Nakatani Y,
Hoshi A, Gorogawa S, Umayahara Y, Itakura Y, Nakagawa T, Taiji M,
Kajimoto Y, Hori M.
Department of Internal Medicine and Therapeutics, Osaka University
Graduate School of Medicine, Suita, Osaka, Japan.
“To elucidate the mechanism of BDNF on glucose metabolism, we
determined the glucose turnover under basal and euglycemic
hyperinsulinemic (insulin infusion rate, 54 pmol. kg(-1). min(-1))
clamp conditions in obese insulin-resistant rats, male Zucker fatty
rats, which had been acutely administered a subcutaneous injection of
BDNF… We conclude that BDNF mainly improves hepatic insulin resistance
in obese insulin-resistant rats, probably by affecting the hepatic GK
[glucokinase] flux.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12601633&dopt=Abstract
d) An earlier, related, paper by the Sumimoto group is available in
full text at no charge:
Diabetes 2000 Mar;49(3):436-44
Brain-derived neurotrophic factor regulates glucose metabolism by
modulating energy balance in diabetic mice.
Nakagawa T, Tsuchida A, Itakura Y, Nonomura T, Ono M, Hirota F, Inoue
T, Nakayama C, Taiji M, Noguchi H.
Sumitomo Pharmaceuticals Research Center, Discovery Research
Laboratories II, Osaka, Japan.
In streptozotocin-induced type 1 diabetic mice “BDNF did not lower
blood glucose concentration but rather enhanced the hypoglycemic
action of insulin. In hyperglycemic db/db mice… BDNF … significantly
restored both pancreatic insulin and glucagon content… [ In] KK mice,
normoglycemic animals with impaired glucose tolerance… BDNF
administration improved insulin resistance in the oral glucose
tolerance test…. we investigated the effect of BDNF on the energy
metabolism of db/db mice. Body temperature and oxygen consumption of
the pellet pair-fed vehicle-treated mice were remarkably lower than
the ad libitum-fed vehicle-treated mice. Daily BDNF administration for
3 weeks completely ameliorated both of the reductions. Finally, to
clarify its action mechanism, the effect of intracerebroventricular
administration of BDNF on db/db mice was examined. Here, a small dose
of BDNF was found to be effective in lowering blood glucose
concentration. This indicates that BDNF regulates glucose metabolism
by acting directly on the brain.”
Full text: http://diabetes.diabetesjournals.org/cgi/reprint/49/3/436
e) Another full text is available on similar effects of ciliary
neurotrophic factor
Proc Natl Acad Sci U S A 1997 Jun 10;94(12):6456-61
Ciliary neurotrophic factor corrects obesity and diabetes associated
with leptin deficiency and resistance.
Gloaguen I, Costa P, Demartis A, Lazzaro D, Di Marco A, Graziani R,
Paonessa G, Chen F, Rosenblum CI, Van der Ploeg LH, Cortese R,
Ciliberto G, Laufer R.
Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), Via
Pontina km 30.600, 00040 Pomezia, Rome, Italy.
http://www.pnas.org/cgi/content/full/94/12/6456
f) A preliminary clinical trial of ciliary neurotrophic factor:
JAMA 2003 Apr 9;289(14):1826-32
Comment in: JAMA. 2003 Apr 9;289(14):1763-4.
Recombinant variant of ciliary neurotrophic factor for weight loss in
obese adults: a randomized, dose-ranging study.
Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH,
Heymsfield SB, Bray GA, Roberts WG, Heyman ER, Stambler N, Heshka S,
Vicary C, Guler HP.
Radiant Research, Stuart, Fla, USA.
“Twelve-week, double-blind, randomized, parallel-group, dose-ranging,
multicenter clinical trial conducted at 2 university obesity clinics
and at 5 independent clinical research clinics from March 2000 to
August 2001, and including 173 nondiabetic obese adults, 82.6% of whom
were women, with a mean (SD) body mass index of 41.1… Recombinant
human variant CNTF was generally well tolerated although adverse
events occurred in 75% of patients receiving placebo and 78% to 93% of
patients receiving rhvCNTF, in a dose-related fashion, with mild
injection site reactions as the most frequently reported adverse
event. CONCLUSIONS: In this initial, dose-ranging, 12-week study,
treatment with rhvCNTF resulted in more weight loss than placebo.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12684362&dopt=Abstract
2. Parkinson’s Disease
a) Ann Neurol 2003;53 Suppl 3:S120-32; discussion S132-4
In vivo gene delivery of glial cell line--derived neurotrophic factor
for Parkinson's disease.
Kordower JH.
Department of Neurological Sciences and Research Center for Brain
Repair, Rush Presbyterian-St. Luke's Medical Center, Chicago IL 60612,
USA.
“this review focuses on in vivo gene delivery of glial cell
line-derived neurotrophic factor (GDNF) as a neuroprotective strategy
for PD.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12666104&dopt=Abstract
b) ICV administration was not found to be helpful:
Neurology 2003 Jan 14;60(1):69-73
Randomized, double-blind trial of glial cell line-derived neurotrophic
factor (GDNF) in PD.
Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER Jr,
Lozano AM, Penn RD, Simpson RK Jr, Stacy M, Wooten GF; ICV GDNF Study
Group. Implanted intracerebroventricular. Glial cell line-derived
neurotrophic factor.
Oregon Health & Science University, Portland 97201-3098, USA
“OBJECTIVE: To assess the safety, tolerability, and biological
activity of glial cell line-derived neurotrophic factor (GDNF)
administered by an implanted intracerebroventricular (ICV) catheter
and access port in advanced PD… A multicenter, randomized,
double-blind, placebo-controlled, sequential cohort study compared the
effects of monthly ICV administration of placebo and 25, 75, 150, 300,
and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months.
An open-label study extended exposure up to an additional 20 months
and maximum single doses of up to 4,000 microg in 16 subjects….
Nausea, anorexia, and vomiting were common hours to several days after
injections of GDNF. Weight loss occurred in the majority of subjects
receiving 75 microg or larger doses of GDNF. Paresthesias, often
described as electric shocks (Lhermitte sign), were common in
GDNF-treated subjects, were not dose related, and resolved on
discontinuation of GDNF. Asymptomatic hyponatremia occurred in over
half of subjects receiving 75 microg or larger doses of GDNF; it was
symptomatic in several subjects…. GDNF administered by ICV injection
is biologically active as evidenced by the spectrum of AE encountered
in this study. GDNF did not improve parkinsonism, possibly because
GDNF did not reach the target tissues--putamen and substantia nigra.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12525720&dopt=Abstract
c) Prog Brain Res 2002;138:421-32
Neuroprotection for Parkinson's disease using viral vector-mediated
delivery of GDNF.
McBride JL, Kordower JH.
Department of Neurological Sciences, Research Center for Brain Repair,
Rush University, 2242 W. Harrison Street, Chicago, IL 60612, USA.
This is a review article for which no abstract is provided.
3. Peripheral neuropathies
a) Rev Neurol (Paris) 2003 Feb;159(2):147-61
[Treatment of peripheral neuropathies with neutrotrophic factors:
animal models and clinical trials]
[Article in French]
Pradat PF.
Federation de Neurologie Mazarin, AP-HP, Hopital de la
Pitie-Salpetriere, Paris, France.
“… NF may be useful in the treatment of peripheral neuropathies.
These pathologies may be more amenable than central nervous diseases
to the systemic delivery of NF… The objectives of NF treatment are: 1)
to compensate a putative deficiency of NF associated with the
pathogenesis of some neuropathies, such as diabetic neuropathy; 2) to
stop or slow disease progression by acting on the biochemical pathways
involved in the neurodegenerative cascade; and 3) to enhance the
physiological compensatory mechanism of axonal sprouting. The efficacy
of treatment with NF has been demonstrated in animal models mimicking
various neuropathies… However, a phase 3 trial in diabetic neuropathy
and a phase 2 trial in HIV-related neuropathy have failed to
demonstrate any substantial effect of treatment with NGF. In this
review, we discuss the factors that may explain these negative
results. A major limitation of systemic administration is the poor
bioavailability of NF due to their short half-life…. In particular,
muscular-based gene therapy allows the delivery of sustained levels of
neurotrophic factor into the circulation. This strategy has shown to
be effective in animal models of motor and sensory neuropathies.
Another promising treatment is the use of small molecules that induce
the endogenous synthesis of NF, such as xaliprodene or
4-methylcathecol.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12660566&dopt=Abstract
More information about the failed trials:
b) Int Rev Neurobiol 2002;50:393-413
Nerve growth factor for the treatment of diabetic neuropathy: what
went wrong, what went right, and what does the future hold?
Apfel SC.
Albert Einstein College of Medicine, Bronx, New York 10461, USA.
… Nerve growth factor (NGF) was the first neurotrophic factor to be
discovered and was one of the earliest to proceed to clinical trials.
NGF, which is selectively trophic for small fiber sensory and
sympathetic neurons, was selected as a potential theraphy for diabetic
polyneuropathy becaus of the serious consequences associated with
degeneration of those neuronal populations in this condition…. Two
sets of phase II clinical trails suggested that recombinant human NGF
(rhNGF) administration was effective at ameliorating the symptoms
associated with both diabetic polyneuropathy and HIV-related
neuropathy. These early studies, however, revealed that painful side
effects were dose limiting for NGF. A large-scale phase III clinical
trail of 1019 patients randomized to receive either rhNGF or placebo
for 48 weeks failed to confirm the earlier indications of efficacy….
As a result of the phase III outcome, Genentech has decided not to
proceed with further development of rhNGF.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12198818&dopt=Abstract
4. Multiple sclerosis
a) Scand J Immunol 2003 May;57(5):493-7
Increased brain-derived neurotrophic factor expression in white blood
cells of relapsing-remitting multiple sclerosis patients.
Gielen A, Khademi M, Muhallab S, Olsson T, Piehl F.
Neuroimmunology Unit, Department of Medicine, Karolinska Institute,
Karolinska Hospital, Stockholm, Sweden.
“we analysed neurotrophin and cytokine mRNA levels…. in unstimulated
peripheral blood mononuclear cells (PBMCs) from multiple sclerosis
(MS) patients in remission and controls. We demonstrate that mRNA for
brain-derived neurotrophic factor (BDNF), but not neurotrophin-3 or
nerve growth factor (NGF), is readily detectable in PBMC and that
levels in MS are increased by approximately 60% compared with patients
with other neurological diseases or healthy subjects. These results
provide additional evidence that a potentially neuroprotective facet
of autoimmune inflammation is present in MS.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12753507&dopt=Abstract
b) Ann Neurol 2003 Mar;53(3):292-304
Neurotrophic cross-talk between the nervous and immune systems:
implications for neurological diseases.
Kerschensteiner M, Stadelmann C, Dechant G, Wekerle H, Hohlfeld R.
Brain Research Institute, University of Zurich and Department of
Biology, ETH Zurich, Switzerland.
“This review focuses on recent findings that immune cells produce
brain-derived neurotrophic factor in multiple sclerosis lesions,
whereas neurons and astrocytes express the appropriate tyrosine kinase
receptor TrkB. Together with functional evidence for the
neuroprotective effects of immune cells, these observations support
the concept of "neuroprotective immunity." We next examine current and
future therapeutic strategies for multiple sclerosis and experimental
autoimmune encephalomyelitis in light of neuroprotective immunity and
finally address the broader implications of this new concept for other
neuroinflammatory and neurodegenerative diseases.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12601697&dopt=Abstract
c) J Neurosci 2002 Nov 1;22(21):9221-7
Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel
role for CNTF and CNTF-related molecules.
Stankoff B, Aigrot MS, Noel F, Wattilliaux A, Zalc B, Lubetzki C.
Biologie des Interactions Neurones-Glie, Institut National de la Sante
et de la Recherche Medicale
Unite 495, Paris cedex 13, France.
“Neurotrophins [NGF, neurotrophin-3 (NT-3), NT-4/5, BDNF], glial cell
line-derived neurotrophic factor (GDNF)-related factors (GDNF,
neurturin), and growth factors such as PDGF-AA, FGF-2, and insulin did
not increase myelinogenesis. In contrast, among factors belonging to
the CNTF family, CNTF, leukemia inhibitory factor, cardiotrophin-1,
and oncostatin M induced a strong promyelinating effect. We provide
evidence that CNTF acts on oligodendrocytes by favoring their final
maturation, and that this effect is mediated through the 130 kDa
glycoprotein receptor common to the CNTF family and transduced through
the Janus kinase pathway.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12417647&dopt=Abstract
d) Trends Immunol 2002 Nov;23(11):512-6
Growth factor treatment of demyelinating disease: at last, a leap into
the light.
Ransohoff RM, Howe CL, Rodriguez M.
Depts of Neurosciences and Nerology, The Cleveland Clinic Foundation,
9500 Euclid Avenue, OH 44195, USA
“… Previous attempts to apply trophic support for oligodendrocytes in
experimental demyelination uniformly produced complicated outcomes
that reflected unexpected effects on immune or inflammatory responses
and could be interpreted only with caution. Now, two recent
publications have demonstrated convincingly that cytokines of the
interleukin (IL)-6 superfamily can ameliorate experimental autoimmune
encephalomyelitis and promote oligodendrocyte survival, without
demonstrable effect on inflammation or immune responses.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12401395&dopt=Abstract
5. Stimulation of neuroprotective activity on brain cells
a) J Neuroimmunol 2003 Mar;136(1-2):67-74
The neuregulin GGF2 attenuates free radical release from activated
microglial cells.
Dimayuga FO, Ding Q, Keller JN, Marchionni MA, Seroogy KB,
Bruce-Keller AJ.
Department of Anatomy and Neurobiology, MN 222 Chandler Medical
Center, University of Kentucky, Lexington 40536-0298, USA.
“The neuregulin glial growth factor 2 (GGF2) is a neural growth factor
that is best known for its ability to promote the survival and
proliferation of oligodendrocytes and Schwann cells. While it has been
shown in recent years that GGF2 is effective in the treatment of
autoimmune models of brain injury, it is not known if the beneficial
effects of GGF2 are based in part on modulation of brain inflammation.
In this report, we document the anti-inflammatory effects of
recombinant human GGF2 (rhGGF2) on microglial free radical production
in vitro…. Overall, these results indicate that the neuregulin rhGGF2
may have anti-inflammatory and antioxidant properties in the brain,
and may also provide trophic support for brain-resident microglial
cells.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12620644&dopt=Abstract
6. Burn Wounds
a) Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2000 Sep;14(5):268-70
[Modulation of nerve growth factor on wound healing of burn]
[Article in Chinese]
Lu GZ, Chen YL, Yang MJ.
Department of Burn Surgery, Wuxi No. 3 People's Hospital, Wuxi
Jiangshu, P. R. China 214041.
“Six domestic pigs weighting around 20 kg were used as experimental
animals…. NGF can not only act directly on burn wound, but also
modulate other growth factors on the burn wound to accelerate the
healing of burn wound.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12516472&dopt=Abstract
b) Zhonghua Shao Shang Za Zhi 2001 Feb;17(1):29-31
[An experimental study on the effects of NGF on the wound healing of
deep partial thickness burn in pigs]
[Article in Chinese]
Lu G, Chen Y, Yang M.
Department of Burns, Wuxi No. 3 People's Hospital. 214041, P.R. China.
“OBJECTIVE: To investigate the effects of nerve growth factor (NGF) on
wound healing of deep partial thickness burn in pigs…. The
proliferation rate of epithelia was much more active in treatment
groups than in control group. Epithelization of the wound in treatment
groups was earlier than of that in control group. The hydroxyproline
content in treatment groups exhibited an increment after a prior
decrement, especially on 5 PBD when the content was much lower in the
treatment groups. The analysis of cellular DNA cycle indicated that
cell number of S phase in treatment groups was obviously more than
that in the control group. Furthermore, the wound healing time in
treatment groups was much shorter than that in control group.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11876907&dopt=Abstract
7. Ischemic stroke
a) Curr Opin Investig Drugs 2002 Dec;3(12):1753-7
Neurotrophins, neuroprotection and the blood-brain barrier.
Pardridge WM.
Department of Medicine, UCLA Warren Hall, 900 Veteran Avenue, Los
Angeles, CA 90024, USA
“…neurotrophins do not cross the … blood-brain barrier (BBB)…. can be
made transportable across the BBB by using chimeric peptide brain drug
targeting technology, in which a neurotrophin is reformulated by
fusion to a transport vector. The latter is a peptide or
peptidomimetic monoclonal antibody that undergoes receptor-mediated
transcytosis through the BBB, and acts as a 'molecular Trojan horse'.
Neurotrophin chimeric peptides are highly neuroprotective following
delayed intravenous administration, in both global and focal brain
ischemia.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12528312&dopt=Abstract
b) Stroke 2001 Jun;32(6):1378-84
Neuroprotection in transient focal brain ischemia after delayed
intravenous administration of brain-derived neurotrophic factor
conjugated to a blood-brain barrier drug targeting system.
Zhang Y, Pardridge WM.
Department of Medicine, University of California at Los Angeles School
of Medicine, Los Angeles, CA 90095-1682, USA.
“…BDNF was conjugated to the OX26 murine monoclonal antibody to the
rat transferrin receptor, which undergoes transport into brain from
blood via the BBB transferrin receptor transcytosis system. After a
1-hour occlusion of the middle cerebral artery in nitrous oxide-
ventilated animals with normal blood sugar, the brain was reperfused,
and either BDNF or the BDNF/OX26 conjugate was administered as a
single intravenous injection at a dose of 50 microg per rat…. These
studies demonstrate marked neuroprotection in focal, transient brain
ischemia with a single, delayed intravenous injection of BDNF if the
neurotrophin is conjugated to a BBB drug targeting system. The
neuroprotection is long lasting and persists for at least 7 days after
a 1-hour middle cerebral artery occlusion.”
Free full text at:
http://stroke.ahajournals.org/cgi/content/full/32/6/1378
8. Spinal cord injuries
a) J Neurotrauma 2002 Sep;19(9):1081-90
Cationic liposome-mediated GDNF gene transfer after spinal cord
injury.
Lu KW, Chen ZY, Jin DD, Hou TS, Cao L, Fu Q.
Department of Spinal Surgery, Southern Hospital, The First Military
Medical University, Guangzhou, China.
“We examined neuroprotective effect of cationic liposome-mediated GDNF
gene transfer in vivo on axonal regeneration and locomotor function
recovery after SCI in adult rats. The mixture of DC-Chol liposomes and
recombinant plasmid pEGFP-GDNF cDNA was injected after SCI. RT-PCR
confirmed the increased expression of GDNF mRNA in the injected areas
at 7 days after injection…. These data demonstrate that in vivo
transfer of GDNF cDNA can promote axonal regeneration and enhance
locomotion functional recovery, suggesting that cationic
liposome-mediated delivery of GDNF cDNA may be a practical gene
transfer method for traumatic SCI treatment.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12482120&dopt=Abstract
b) Exp Neurol 2002 Sep;177(1):265-75
Transplants of fibroblasts genetically modified to express BDNF
promote axonal regeneration from supraspinal neurons following chronic
spinal cord injury.
Jin Y, Fischer I, Tessler A, Houle JD.
Department of Anatomy and Neurobiology, University of Arkansas for
Medical Sciences, Little Rock, Arkansas 72205, USA.
“Transplants of fibroblasts genetically modified to express BDNF
(Fb/BDNF) have been shown to promote regeneration of rubrospinal axons
and recovery of forelimb function when placed acutely into the injured
cervical spinal cord of adult rats. Here we investigated whether
Fb/BDNF cells could stimulate supraspinal axon regeneration and
recovery after chronic (4 week) injury…. These results demonstrate
that fibroblasts genetically modified to express BDNF promote axon
regeneration from supraspinal neurons in the chronically injured
spinal cord with accompanying partial recovery of locomotor
performance.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12429228&dopt=Abstract
c) J Neuropathol Exp Neurol 2002 Feb;61(2):142-53
Effects of brain-derived neurotrophic factor (BDNF) on
compression-induced spinal cord injury: BDNF attenuates
down-regulation of superoxide dismutase expression and promotes
up-regulation of myelin basic protein expression.
Ikeda O, Murakami M, Ino H, Yamazaki M, Koda M, Nakayama C, Moriya H.
Department of Orthopedic Surgery, Graduate School of Medicine, Chiba
University, Japan.
“…The effects of intrathecally administered BDNF on both Cu/Zn
superoxide dismutase (CuZnSOD) and myelin basic protein (MBP)
expression were examined using rats that had received
compression-induced spinal cord injury. CuZnSOD expression in the
spinal cord was down-regulated within 24 h of compression-induced
injury and then recovered. Continuous infusion of BDNF inhibited the
acute down-regulation of CuZnSOD expression. In situ hybridization
showed that CuZnSOD was expressed in both neurons and glia. Although
MBP expression was greatly reduced after injury, BDNF administration
promoted the recovery of MBP expression nearly to a control level
after 2 wk. Furthermore, BDNF administration also prompted behavioral
recovery. These results suggest BDNF's usefulness in human clinical
applications”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11853017&dopt=Abstract
9. Other nerve regeneration
a) J Neurosci Res 2002 Dec 15;70(6):746-55
Glial cell line-derived neurotrophic factor released by synthetic
guidance channels promotes facial nerve regeneration in the rat.
Barras FM, Pasche P, Bouche N, Aebischer P, Zurn AD.
Department of ENT and Head and Neck Surgery, University Medical
School, Lausanne, Switzerland.
“…the potential accelerating and maturating effects of the
neurotrophic factors glial cell line-derived neurotrophic factor
(GDNF) and neurotrophin-3 (NT-3) on nerve regeneration were assessed
using an axotomy model of the rat facial nerve…. These results
demonstrate that GDNF, as previously described for the sciatic nerve,
a mixed sensory and motor nerve, is also very efficient in promoting
regeneration of the facial nerve, an essentially pure motor nerve.
GDNF may therefore be useful in improving facial nerve regeneration in
the clinic.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12444596&dopt=Abstract
b) J Hand Surg [Am] 2001 May;26(3):478-88
Axonal regeneration stimulated by the combination of nerve growth
factor and ciliary neurotrophic factor in an end-to-side model.
McCallister WV, Tang P, Smith J, Trumble TE.
Department of Orthopaedics, University of Washington School of
Medicine, Seattle, WA 98195-6500, USA.
“The aim of this study was to investigate the potential for
stimulating axonal regeneration in the context of end-to-side
coaptation using a combination of nerve growth factor and ciliary
neurotrophic factor in the rat sciatic nerve model…. These data
support the conclusion that the use of nerve growth factor and ciliary
neurotrophic factor in combination may enhance regeneration in the
peripheral nervous system”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11418911&dopt=Abstract
10. Angiogenesis
a) Arch Dis Child 2002 Nov;87(5):446-8
Improving ischaemic skin revascularisation by nerve growth factor in a
child with crush syndrome.
Chiaretti A, Piastra M, Caresta E, Nanni L, Aloe L.
Pediatric Intensive Care Unit, Catholic University Medical School,
Rome, Italy.
“Recent studies suggest that NGF influences endothelial cell
proliferation and angiogenic activity. In view of these proposed
regenerative effects, we evaluated the efficacy of subcutaneous
administration of highly purified murine NGF in a child with severe
crush syndrome of the lower left limb. NGF 10 micro g was administered
subcutaneously every eight hours for seven days to the extensive
ischaemic skin lesion of the calcaneal area. After treatment we
observed gradual improvement of the ischaemic area; no side effects
were noted.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12390930&dopt=Abstract
b) Neurosci Lett 2002 Apr 26;323(2):109-12
Nerve growth factor induces angiogenic activity in a mouse model of
hindlimb ischemia.
Turrini P, Gaetano C, Antonelli A, Capogrossi MC, Aloe L.
Laboratorio di Patologia Vascolare, Istituto Dermopatico
dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico,
Via dei Monti di Creta 104, 00167 Rome, Italy.
“In the present study, it was investigated whether NGF exhibits an
angiogenic effect in a mouse model of hindlimb ischemia induced by
femoral artery occlusion…. Furthermore, exogenous NGF, administered
subcutaneously for 7 days in ischemic hindlimb, induced a marked
increase of arteriole length density… However, capillaries were not
significantly increased”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11950505&dopt=Abstract
11. Retinitis pigmentosa and other retinal degeneration
a) Invest Ophthalmol Vis Sci 2002 Oct;43(10):3292-8
Encapsulated cell-based delivery of CNTF reduces photoreceptor
degeneration in animal models of retinitis pigmentosa.
Tao W, Wen R, Goddard MB, Sherman SD, O'Rourke PJ, Stabila PF, Bell
WJ, Dean BJ, Kauper KA, Budz VA, Tsiaras WG, Acland GM, Pearce-Kelling
S, Laties AM, Aguirre GD.
Neurotech USA, Lincoln, Rhode Island 02865, USA.
“PURPOSE: The objective of the present study was to evaluate the
therapeutic efficacy of ciliary neurotrophic factor (CNTF) delivered
through encapsulated cells directly into the vitreous of the eye in an
rcd1 canine model of retinitis pigmentosa… CNTF delivered through
encapsulated cells directly into the vitreous of the eye protects
photoreceptors in the PDE6B-deficient rcd1 canine model. Furthermore,
sparing of photoreceptors appeared dose-dependent with minimum
protection observed at CNTF doses of 0.2 to 1.0 ng/d. Incrementally
greater protection was achieved at higher doses. The surgically
implanted, cell-containing capsules were well tolerated, and the cells
within the capsule remained viable for the 7-week implantation
interval. These results suggest that encapsulated cell therapy may
provide a safe and effective strategy for treating retinal disorders
in humans.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12356837&dopt=Abstract
b) Neurosci Lett 2001 Jun 8;305(2):139-42
Patterns of retinal ganglion cell survival after brain-derived
neurotrophic factor administration in hypertensive eyes of rats.
Ko ML, Hu DN, Ritch R, Sharma SC, Chen CF.
Department of Physiology, National Taiwan University, 1, Section 1,
Jen-Ai Road, 10018, Taipei, Taiwan.
“These findings demonstrated that BDNF has partial neuroprotection on
RGCs in whole retina and enhances RGC survival in moderately chronic
hypertensive eyes.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11376903&dopt=Abstract
c) Invest Ophthalmol Vis Sci 2000 Sep;41(10):2967-71
The combined effect of brain-derived neurotrophic factor and a free
radical scavenger in experimental glaucoma.
Ko ML, Hu DN, Ritch R, Sharma SC.
Department of Physiology, National Taiwan University, Taipei.
“Brain-derived neurotrophic factor (BDNF) had a limited effect on the
survival of retinal ganglion cells (RGCs) in rats' eyes with elevated
intraocular pressure (IOP). The combined treatment of BDNF and a
nonspecific free radical scavenger
N-tert-butyl-(2-sulfophenyal)-nitrone (S-PBN) was investigated on the
RGCs in hypertensive eyes of rats. … Trophic factors and antioxidants
have synergistic effects on rescuing RGCs from death in eyes with
elevated IOP. Further studies of different combined treatment
therapies may provide avenues to save RGCs from death in eyes with
elevated IOP.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10967052&dopt=Abstract
12 Neonatal plexopathies
a) Plast Reconstr Surg 2002 Sep 15;110(4):1066-72
Simultaneous GDNF and BDNF application leads to increased motoneuron
survival and improved functional outcome in an experimental model for
obstetric brachial plexus lesions.
Aszmann OC, Korak KJ, Kropf N, Fine E, Aebischer P, Frey M.
Division of Plastic and Reconstructive Surgery, Department of Surgery,
Medical School, University of Vienna, Vienna, Austria.
“Recent studies showed that both glial cell-line-derived neurotrophic
factor (GDNF) and brain-derived neurotrophic factor (BDNF) reduce
induced degeneration of motoneurons after axotomy and avulsion… the
authors have used a proximal crush lesion of the brachial plexus in
neonatal rats as the experimental model of neuronal injury. This
allowed the authors to study the effects of trophic factor
administration on injured motoneurons and the relationship between
motoneuron survival and extremity function. Trophic factors were
locally released by small polymer implants in a low-dose slow-release
mode…. The authors conclude that a combination of trophic factors
leads to enhanced motoneuron survival, with improved voluntary
function as the animal enters adulthood so that exogenous trophic
support of motoneurons might have a role in the treatment of all types
of severe neonatal plexopathies, maintaining the viability of
motoneurons until reconstructive surgery provides them with a pathway
for regeneration and endogenous trophic support.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12198419&dopt=Abstract
13. Huntington's disease
a) J Neurosci 2002 Jun 1;22(11):4478-86
Corticostriatopallidal neuroprotection by adenovirus-mediated ciliary
neurotrophic factor gene transfer in a rat model of progressive
striatal degeneration.
Mittoux V, Ouary S, Monville C, Lisovoski F, Poyot T, Conde F,
Escartin C, Robichon R, Brouillet , Peschanski M, Hantraye P.
Unite de Recherche Associee 2210, Commissariat a l'Energie Atomique,
Centre National de la Recherche Scientifique, Service Hospitalier
Frederic Joliot, 91401 Orsay Cedex, France.
“We explored the potential of adenovirus-mediated gene transfer to
fulfill these requirements by studying the functional and anatomical
effects of single-site striatal delivery of CNTF recombinant vectors
in a rat model of HD…. Overall, adenovirus-mediated CNTF gene transfer
appears to be a potentially useful delivery system for widespread,
long-term circuit neuroprotection in HD patients.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12040055&dopt=Abstract
b) Brain Res Bull 2002 Apr;57(6):817-22
Neuroprotection by neurotrophins and GDNF family members in the
excitotoxic model of Huntington's disease.
Alberch J, Perez-Navarro E, Canals JM.
Departament de Biologia Cel.lular i Anatomia Patologica, Facultat de
Medicina, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
“…In conclusion, the trophic requirements of each population of
striatal projection neurons are due to a complex interaction between
several neurotrophic factors, such as neurotrophins and GDNF family
members, which can be modified, in different pathological conditions.
Moreover, these neurotrophic factors may be able to provide selective
protection for basal ganglia circuits, which are affected in
striatonigral degenerative disorders, such as Huntington's disease or
multisystem atrophy.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12031278&dopt=Abstract
14. Depression
a) J Neurosci 2002 Apr 15;22(8):3251-61
Brain-derived neurotrophic factor produces antidepressant effects in
behavioral models of depression.
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS.
Division of Molecular Psychiatry, Abraham Ribicoff Research
Facilities, Connecticut Mental Health Center, Yale University School
of Medicine, New Haven, Connecticut 06508, USA.
“…in behavioral models of depression, the learned helplessness (LH)
and forced swim test (FST) paradigms. A single bilateral infusion of
BDNF [brain-derived neurotrophic factor] into the dentate gyrus of
[rat] hippocampus produced an antidepressant effect in both the LH and
FST that was comparable in magnitude with repeated systemic
administration of a chemical antidepressant. These effects were
observed as early as 3 d after a single infusion of BDNF and lasted
for at least 10 d. Similar effects were observed with neurotrophin-3
(NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not
influence locomotor activity or passive avoidance.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11943826&dopt=Abstract
b) Psychiatry Res 2002 Mar 15;109(2):143-8
Decreased serum brain-derived neurotrophic factor levels in major
depressed patients.
Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM.
Laboratory of Biochemistry, Division of Neuropsychiatry, Geneva
University Hospitals, 2 chemin du Petit Bel-Air, CH-1225 Chene-Bourg,
Switzerland
“These results suggest that major depression is characterized by low
serum BDNF levels and support the hypothesis of neurotrophic factor
involvement in affective disorders.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11927139&dopt=Abstract
15 Hearing impairment
a) Neurosci Lett 2002 Mar 22;321(3):149-52
Herpes simplex virus type 1-mediated transfer of neurotrophin-3
stimulates survival of chicken auditory sensory neurons.
Carnicero E, Knipper M, Tan J, Alonso MT, Schimmang T.
Instituto de Biologia y Genetica Molecular, Universidad de Valladolid
y Consejo Superior de Investigaciones Cientificas, Departamento de
Bioquimica, Biologia Molecular y Fisiologia, Facultad de Medicina,
47005 Valladolid, Spain.
“In the present report, we have produced a HSV-1-based amplicon vector
expressing NT-3. This vector efficiently infects isolated auditory
neurons and stimulates their survival during distinct developmental
stages of the inner ear. Therefore, this vector may present a unique
entry point to develop therapies preventing or treating hearing
impairment caused by the degeneration of auditory neurons.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11880194&dopt=Abstract
16 Neuropathic pain
a) Curr Opin Pharmacol 2001 Feb;1(1):66-72
Neurotrophic factors and neuropathic pain.
Boucher TJ, McMahon SB.
Sensory Function Group, Centre for Neuroscience Research, London, UK.
“…Neurotrophic factors have been shown to be neuroprotective for
damaged sensory neurones, providing a rationale for testing their
effects in neuropathic pain states. Recent data have demonstrated
potent analgesic effects of one factor (glial cell line-derived
neurotrophic factor) in animal models of neuropathy, and implicated
changes in sodium channel alpha-subunits in the generation of afferent
ectopic activity. The new findings provide a rational basis for the
use of neurotrophic factors as a novel therapeutic treatment for
neuropathic pain states.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11712538&dopt=Abstract
17. Amyotrophic lateral sclerosis
a) Amyotroph Lateral Scler Other Motor Neuron Disord 2000
Jun;1(3):201-6
A phase I/II trial of recombinant methionyl human brain derived
neurotrophic factor administered by intrathecal infusion to patients
with amyotrophic lateral sclerosis.
Ochs G, Penn RD, York M, Giess R, Beck M, Tonn J, Haigh J, Malta E,
Traub M, Sendtner M, Toyka KV.
Department of Neurology, Julius-Maximilians University, Wurzburg,
Germany.
“Within days after the initiation of infusion the majority of patients
receiving r-metHuBDNF reported mild sensory symptoms, including
paraesthesias or a sense of warmth, which were usually confined to the
lower limbs and were frequently exacerbated by neck flexion. In most
instances these symptoms decreased or even disappeared over several
weeks. Sleep disturbance, dry mouth, agitation and other behavioural
effects were encountered at higher doses (>150 microg/day) and
necessitated dose reductions…. The intrathecal delivery of r-metHuBDNF
in doses of up to 150 microg/day was well tolerated and appears
feasible. The reversible CNS effects with higher dose indicate that
BDNF can be delivered cranially against CSF flow. The small number of
patients and the design of the study did not permit conclusions to be
drawn about the efficacy of the treatment.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11464953&dopt=Abstract
b) Cochrane Database Syst Rev 2002;(3):CD002064
Recombinant human insulin-like growth factor I (rhIGF-I) for
amyotrophic lateral sclerosis/motor neuron disease.
Mitchell JD, Wokke JH, Borasio GD.
Department of Neurology, Royal Preston Hospital, Sharoe Green Lane,
Fulwood, Preston, UK, PR2 9HT.
“BACKGROUND: Trophic factors, including recombinant human insulin-like
growth factor I have been postulated as possible disease modifying
therapies for amyotrophic lateral sclerosis. Randomised clinical
trials of recombinant human insulin-like growth factor I in
amyotrophic lateral sclerosis to date have yielded conflicting
results. OBJECTIVES: The main objective of this review was to examine
the efficacy of recombinant human insulin-like growth factor I in
amyotrophic lateral sclerosis. Occurrence of adverse events has also
been reviewed…. REVIEWER'S CONCLUSIONS: Recombinant human insulin-like
growth factor I may be modestly effective but the evidence currently
available is insufficient for a definitive assessment. Further
randomised clinical trials need to be done.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12137643&dopt=Abstract
c) However, the summary of a meeting on neurotrophins held in 2002
mentions that clinical trials in this area have not been successful
http://www.weizmann.ac.il/Biological_Chemistry/scientist/Fainzilber/NGF2002-Mtg-Report.pdf
18 Cystitis? (no abstract available, so it is not possible to tell
whether positive or negative results are being reported)
Urology 2001 Jun;57(6 Suppl 1):118-9
Recombinant human nerve growth factor in the treatment of interstitial
cystitis: preliminary results.
Dimitrakov J, Tchitalov J, Zlatanov T, Dikov D, Rawadi G.
Justus-Liebig University, Urology Clinic, Giessen, Germany.
Publication Types: * Clinical Trial * Randomized Controlled Trial
19. Alternatives to autologous nerve grafts
a) Arch Otolaryngol Head Neck Surg 2001 Mar;127(3):294-8
Brain-derived neurotrophic factor-enriched collagen tubule as a
substitute for autologous nerve grafts.
Terris DJ, Toft KM, Moir M, Lum J, Wang M.
Division of Otolaryngology/Head and Neck Surgery, Stanford University
Medical Center, Edwards Bldg, Room R135, Stanford, CA 94305-5328, USA.
“Collagen tubules filled with BDNF-enriched collagen gel appear to be
at least as good as autologous nerve grafts for bridging short facial
nerve gaps. Larger experimental studies are warranted to determine if
clinical trials are justified.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11255474&dopt=Abstract
b) Laryngoscope 1999 Sep;109(9):1412-6
A novel, biodegradable polymer conduit delivers neurotrophins and
promotes nerve regeneration.
Hadlock T, Sundback C, Koka R, Hunter D, Cheney M, Vacanti J.
Department of Otolaryngology, Massachusetts Eye and Ear Infirmary,
Boston 02114, USA.
“…Inosine, a purine analogue thought to promote axonal extension
following neural injury, was loaded into cylindrical polymer foams
composed of a polylactide-co-glycolide copolymer. First, in vitro
extravasation of inosine was measured over a several week period using
spectrophotometry. Second, the foams were fashioned into
single-channel cylindrical nerve guidance conduits via a novel,
low-pressure injection molding technique. The conduits were then used
to bridge 7-mm defects in the rat sciatic nerve… A nerve regeneration
conduit was successfully created that delivers growth promoting
substances over a protracted time course. In an in vivo model, the
presence of inosine, a purine analogue, yielded neural regeneration
whose histological features suggest possible superior long-term motor
function.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10499046&dopt=Abstract
20 Alzheimer’s Disease
a) Cell Transplant 2000 Sep-Oct;9(5):629-36
Intraparenchymal NGF infusions rescue degenerating cholinergic
neurons.
Tuszynski MH.
Department of Neurosciences, University of California-San Diego, La
Jolla 92093-0626, USA.
“The present study examined whether intraparenchymal infusions of NGF
adjacent to cholinergic neuronal soma are an effective and
well-tolerated means of providing NGF to degenerating cholinergic
neurons. Cholinergic neuronal rescue together with axonal sprouting
responses and local tissue damage in the brain were assessed in adult
rats that underwent complete unilateral fornix transections, followed
by intraparenchymal infusions of recombinant human NGF for a 2-week
period…. Intraparenchymal NGF delivery merits further study at longer
term time points as a means of treating the cholinergic component of
neuronal loss in Alzheimer's disease.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11144960&dopt=Abstract
b) Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S39-46
Neurotrophic factor strategies for the treatment of Alzheimer disease.
Nabeshima T, Yamada K.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya
University Graduate School of Medicine, Japan.
“…Experimental studies demonstrated that a continuous infusion of
nerve growth factor into the cerebroventricle prevents cholinergic
neuron atrophy after axotomy or associated with normal aging and
ameliorates cognition impairment in these animals. A clinical study in
three patients with Alzheimer disease revealed, however, that a
long-term intracerebroventricular infusion of nerve growth factor may
have certain potentially beneficial effects, but the continuous
intracerebroventricular route of administration is also associated
with negative side effects that appear to outweigh the positive
effects. Several other strategies have been suggested to provide
neurotrophic support to cholinergic neurons. In this article, we
review the neurotrophic factor strategies for the treatment of
Alzheimer disease.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10850729&dopt=Abstract
c) Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S31-8
Nerve growth factor treatment in dementia.
Jonhagen ME.
Department of Clinical Neuroscience, Karolinska Institute, Huddinge
University Hospital, Sweden.
“…Data from animal studies, as well as from the author's recent
clinical trial, in which NGF was infused to the lateral ventricle in
patients with Alzheimer disease, will be presented. Effects of NGF on
cognition, as well as issues regarding dosage, side effects, and
alternative ways of administering NGF, will be discussed.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10850728&dopt=Abstract
21 Vasculitic ulcers
a) Lancet 2000 Nov 18;356(9243):1739-40
NGF, a useful tool in the treatment of chronic vasculitic ulcers in
rheumatoid arthritis.
Tuveri M, Generini S, Matucci-Cerinic M, Aloe L.
“We treated chronic vasculitic leg ulcers in rheumatoid arthritis and
systemic sclerosis by topical application of nerve growth factor
(NGF). In all patients with rheumatoid arthritis, NGF led to rapid
healing, whereas less striking results were obtained in patients with
systemic sclerosis. …We suggest that topical application of NGF could
represent a powerful pharmacological tool for the treatment of
vasculitic ulcers.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11095266&dopt=Abstract
22 Corneal ulcers / keratitis
a) Arch Ophthalmol 2000 Oct;118(10):1446-9
Anti-inflammatory and healing properties of nerve growth factor in
immune corneal ulcers with stromal melting.
Lambiase A, Bonini S, Aloe L, Rama P, Bonini S.
Institute of Neurobiology, National Research Council, Viale Marx
15/43, 00137 Rome, Italy.
No abstract provided
b) Ophthalmology 2000 Jul;107(7):1347-51;
Topical treatment with nerve growth factor for neurotrophic keratitis.
Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L.
Department of Ophthalmology, University of Rome "Tor Vergata" and the
G. B. Bietti Eye Foundation, Rome, Italy.
“… Forty-five eyes of 43 consecutive patients with moderate (stage 2,
n = 17) to severe (stage 3, n = 28) neurotrophic keratitis
unresponsive to other nonsurgical therapies…. Nerve growth factor eye
drops improved corneal sensitivity and promoted corneal epithelial
healing in both moderate and severe neurotrophic keratitis. Although
performed in an uncontrolled and nonrandomized series of patients,
this therapy shows promise for the restoration of ocular surface
integrity and visual function in neurotrophic corneal disease.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10889110&dopt=Abstract
23 Stimulation of gut motility
a) Gastroenterology 2000 Jul;119(1):41-50
Recombinant human neurotrophic factors accelerate colonic transit and
relieve constipation in humans.
Coulie B, Szarka LA, Camilleri M, Burton DD, McKinzie S, Stambler N,
Cedarbaum JM.
Gastroenterology Research Unit, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota, USA.
“The aim of this study was to assess the effects of recombinant human
brain-derived neurotrophic factor (r-metHuBDNF) and recombinant human
neurotrophic factor 3 (r-metHuNT-3) on gastrointestinal motor
functions in healthy people and in patients with constipation….
r-met-HuBDNF accelerated overall and proximal colonic emptying
(P<0.05) in health. r-metHuNT-3 accelerated overall colonic transit in
health and constipation (all P<0.05) and gastric and small bowel
transit (both P<0.05) in health. r-metHuBDNF tended to increase stool
frequency compared with placebo in health (P = 0.09). r-metHuNT-3
increased stool frequency (P = 0.05) and facilitated passage of stool
(P < 0.01) in constipated patients.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10889153&dopt=Abstract
24 Muscular strain injuries
a) Clin Orthop 2000 Jan;(370):272-85
Use of growth factors to improve muscle healing after strain injury.
Kasemkijwattana C, Menetrey J, Bosch P, Somogyi G, Moreland MS, Fu FH,
Buranapanitkit B, Watkins SS, Huard J.
Department of Orthopaedic Surgery, University of Pittsburgh, PA 15261,
USA.
“…Several growth factors capable of improving muscle regeneration were
investigated; basic fibroblast growth factor, insulin-like growth
factor, and nerve growth factors were identified as substances capable
of enhancing muscle regeneration and improving muscle force in the
strained injured muscle. The current study should aid in the
development of strategies to promote efficient muscle healing and
complete recovery after strain injury.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10660723&dopt=Abstract
25 Pressure ulcers
a) Lancet 1999 Jul 24;354(9175):307
Effect of topical application of nerve-growth factor on pressure
ulcers.
Bernabei R, Landi F, Bonini S, Onder G, Lambiase A, Pola R, Aloe L.
“Pressure ulcer is a frequent problem in frail older people, with
serious consequences and high costs. Topical application of nerve
growth factor promotes skin ulcer healing.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10440316&dopt=Abstract
26 Bone fractures
a) J Orthop Res 1997 Mar;15(2):235-42
Topical application of nerve growth factor improves fracture healing
in rats.
Grills BL, Schuijers JA, Ward AR.
School of Human Biosciences, La Trobe University, Bundoora, Victoria,
Australia.
“After fracture of a rib in male rats, nerve growth factor was
delivered by a miniosmotic pump to the fracture site for 7 days at the
rate of 1.4 micrograms/day… By 42 days, there was only bony callus
between the fracture ends in both the control group and the treated
group. The treated group, however, again showed significantly elevated
concentrations of norepinephrine and epinephrine (286 and 382%,
respectively) and significantly elevated breaking stress (50%) and
Young's modulus (51%), together with a reduction in the transverse
cross-sectional area of the repair site (57%). The resultant increases
in effectiveness and rate of repair of bone with administration of
nerve growth factor suggest that it may play an important role in the
healing processes of fractured bone.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9167626&dopt=Abstract
27 HIV-associated dementia
a) J Neurochem 2001 Aug;78(4):1-17
Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear
factor-kappaB (NF-kappaB)-dependent mechanism.
Ramirez SH, Sanchez JF, Dimitri CA, Gelbard HA, Dewhurst S, Maggirwar
SB.
Department of Microbiology and Immunology, University of Rochester
Medical Center, Rochester, New York, USA.
“…Tat-induced neuronal apoptosis in primary cultures of rat cerebellar
granule cells and in neuronally differentiated human SK-N-MC cells is
profoundly inhibited by brain-derived neurotrophic factor, nerve
growth factor and activity-dependent neurotrophic factor nonamer
peptide…. These findings suggest that the activation of NF-kappaB by
neurotrophic factors may promote survival of neurons exposed to Tat,
via regulation of anti-apoptotic genes including Bcl-2.”
Full text at:
http://128.151.62.33/pdf/JNC01.pdf
In addition:
1. Regulation of cell survival by secreted proneurotrophins
R Lee, P Kermani, K K Teng, B L Hempstead
Science, 30 Nov 2002, 1945-1948
full text at:
http://hsc.virginia.edu/medicine/basic-sci/neurosci/mkw/pdfs/Lee1023.pdf
A report on this work on the Cornell web site at:
http://www.news.cornell.edu/Chronicles/1.17.02/neurotrophins.html
summarizes the main findings and mentions additional potential
therapeutic areas of atherosclerosis and cancer:
“What Hempstead and colleagues in her laboratory found was that the
same class of growth factors, at different stages of their synthesis,
can have opposite effects. That is, the initial forms of neurotrophins
-- or proneurotrophins -- bind to a receptor called p75, leading to
apoptosis, or cell death. Meanwhile, the mature (cleaved)
neurotrophins interact with trk (pronounced "track") receptors,
leading to cell survival and, when blood vessels are injured, to
responses to that injury.
…
Hempstead's work suggests a potential mechanism by which diseases such
as Alzheimer's may progress, as well as potential strategies by which
a person's risk for those diseases might be measured, or by which the
disease might even be treated. The goal would be to find specific
drugs that would lower the levels of proneurotrophins and raise the
levels of cleaved neurotrophins in the appropriate parts of the
nervous system.
…
Hempstead's findings have important implications for the understanding
and treatment of atherosclerosis, as well as for the important field
of blood vessel formation, or angiogenesis. To combat atherosclerosis,
strategies using neurotrophins could be employed to promote blood
vessel growth in regions where the blood supply has been compromised
by atherosclerotic disease.
…
To fight cancer, a useful strategy may be to promote the binding of
proneurotrophins and p75 receptors in the appropriate tissues -- to
promote the dying off of cancerous cells. And, in fact, the
investigators modified natural proneurotrophin to produce a novel,
cleavage-resistant proneurotrophin, suggesting a potential strategy
for the creation of a new kind of anti-tumor drug.”
And general papers on potential methods of delivery:
a) Biomaterials 2002 Sep;23(17):3765-72
Polyphosphoester microspheres for sustained release of biologically
active nerve growth factor.
Xu X, Yu H, Gao S, Ma HQ, Leong KW, Wang S.
Molecular & Bio-Materials Lab, Institute of Materials Research &
Engineering, National University of Singapore, Singapore.
“These results demonstrated the feasibility of using biodegradable
PPEs for microencapsulation of NGF and provided a basis for future
therapeutic application of the microspheres.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12109702&dopt=Abstract
b) J Control Release 2001 Jan 29;70(1-2):29-36
Simultaneous delivery of an active protein and neutralizing antibody:
creation of separated regions of biological activity.
Fleming AB, Saltzman WM.
School of Chemical Engineering, 120 Olin Hall, Cornell University,
Ithaca, NY 14853, USA.
“…Two-layer polymer matrices that simultaneously released NGF and a
neutralizing antibody (anti-NGF) from opposite faces were placed in
PC12 cell-populated collagen gels… These experiments suggest that
spatial control over the biological activity of a potent agent can be
obtained by an appropriately designed controlled-release device.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11166405&dopt=Abstract
c) J Control Release 2000 Oct 3;69(1):149-58
Controlled release of nerve growth factor from a heparin-containing
fibrin-based cell ingrowth matrix.
Sakiyama-Elbert SE, Hubbell JA.
Department of Materials and Institute for Biomedical Engineering,
ETH-Zurich and University of Zurich, Zurich, Switzerland.
“The goal of this work was to develop a growth factor delivery system
for use in nerve regeneration that would provide localized release of
beta-nerve growth factor (beta-NGF) and other members of the
neurotrophin family in a controlled manner…. we used a
heparin-containing fibrin-based cell ingrowth matrix consisting of
three components, namely an immobilized heparin-binding peptide,
heparin and a neurotrophin with low heparin-binding affinity. The
heparin-binding peptide contained a factor XIIIa substrate and was
covalently cross-linked to fibrin matrices during polymerization. This
cross-linked heparin-binding peptide served to immobilize heparin
within the matrix, and this immobilized heparin interacted with the
neurotrophin and slowed the passive release of the growth factor from
the matrix…. The results suggest that these matrices could serve as
therapeutic materials to enhance peripheral nerve regeneration through
nerve guide tubes and may have more general usefulness in tissue
engineering for the delivery of non-heparin-binding growth factors.”
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11018553&dopt=Abstract
Search strategy:
I started by looking on Medline
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
First I selected the MeSH database from the link in the left-hand
navigation bar, and searched on neurotrophins. This gave me the
information that Medline uses the index term “nerve growth factors”
It also told me that there are a number of subheadings:
Brain-Derived Neurotrophic Factor
Ciliary Neurotrophic Factor
Glia Maturation Factor
Nerve Growth Factor
Neuregulins
Neuregulin-1
Neurotrophin 3
so I “exploded” the search, in order to cover all these as well
(“explode” is the default when you select a search term via the MeSH
Database). At the same time, I restricted the search to articles in
which this term is used to describe the major topic of the article.
This gave over 10,000 hits so I restricted the search further to the
qualifier “therapeutic use” (both these restrictions are done from
within the MeSH database page, and then the search term is sent to the
PubMed search box). This resulted in 343 hits. I did not restrict the
search to human studies only, because animal studies will also be
relevant to a consideration of potential uses of these compounds in
the future.
I also did a backup search on Google using the search terms:
therapeutic potential neurotrophins
I hope this is the sort of information you were seeking, but please
use the clarification feature if you require any more.
Best wishes
tehuti |
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