Tyrosine phosphatase inhibition enhances neurotrophin potency and rescues nigrostriatal neurons in adult rats.
Neurotrophic factors regulate a variety of cellular processes, including neuronal survival during development and after injury. For instance, brain-derived neurotrophic factor (BDNF) can prevent the death of dopaminergic substantia nigra neurons in rats. Most neurotrophic factor receptors, such as TrkB for BDNF, are tyrosine kinases whose signaling is terminated by protein tyrosine phosphatases (PTPs). We tested the idea that inhibition of PTPs, and thus potentially enhancement of the efficiency of endogenous trophic factors and their receptors, would lead to increased neuronal survival. After a 2-week infusion of the small PTP inhibitor molecule peroxovanadium (pVa, pervanadate) close to the substantia nigra of adult rats, up to 66% of axotomized substantia nigra neurons had survived, compared to only 33% in control rats infused with PBS. PVa most likely affected TrkB and/or downstream signaling molecules, as ineffective doses of BDNF and pVa had a synergistic effect when given simultaneously, rescuing 82% of the neurons. PVa stimulated tyrosine hydroxylase (TH) expression in the noninjured substantia nigra but did not prevent axotomy-induced loss of TH. These results raise the possibility that PTP inhibition can prevent neuronal death by enhancing neurotrophic factor signaling pathways in the adult mammalian nervous system, identifies an important role for PTPs in neuronal functioning, and points to a novel small molecule treatment approach for neurologic disorders
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Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Maysinger
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Hagg
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D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007276:Injections, Intraventricular; D009414:Nerve Growth Factors / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D020734:Parkinsonian Disorders / Q000201:enzymology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology*; D014638:Vanadates / Q000008:administration & dosage
D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; C069276:peroxovanadate; D014638:Vanadates; D020813:Receptor, trkB; D017027:Protein Tyrosine Phosphatases