Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy.
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative disorders, although there is no drug or therapeutic treatment to demonstrate disease-modifying effects. Previous work has proposed that neurodegeneration is linked to a lack of trophic support in those neurons and brain areas associated with PD and AD. Indeed, previous studies have found that neurotrophic factors (NTFs) support neuronal survival in various cellular and animal models of PD and AD. Thus, attention has begun to turn to the possibility of NTF neuroprotective-neurorescue therapies for these diseases, indicating that NTFs may be of significant clinical importance as exogenously supplied or endogenously induced elements that obliterate neuronal deficits and degeneration. We have recently reported that the anti-PD drug rasagiline, the anti-AD drug ladostigil, and their propargyl moiety, propargylamine, enhanced the expression levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, endogenous NTFs associated with activation of phosphatidylinositol 3-kinase, protein kinase, and mitogen-activated protein kinase cell signaling/survival pathways. These studies indicate that the induction of NTFs by rasagiline and ladostigil might suppress apoptosis and induce neurorescue in neurodegenerative disorders and may support the drugs' possible disease-modifying mechanism of action.
Weinreb
Orly
O
Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, P.O. Box 9697, 31096 Haifa, Israel.
Amit
Tamar
T
Bar-Am
Orit
O
Youdim
Moussa B H
MB
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline