title: ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats.
abstract: Oxidative stress and neuroinflammation are known causative factors in progressive degeneration of dopaminergic (DAergic) neurons in Parkinson's disease (PD). Neural stem cells (NSCs) contribute in maintaining brain plasticity; therefore, survival of NSCs and neuroblasts during neurodegenerative process becomes important in replenishing the pool of mature neuronal population. Acetyl-L-carnitine (ALCAR), present in almost all body cells, increases endogenous antioxidants and regulates bioenergetics. Currently, no information is available about the putative mechanism and neuroprotective effects of ALCAR in 6-hydroxydopamine (6-OHDA)-induced rat model of PD-like phenotypes. Herein, we investigated the effect of ALCAR on death/survival of DAergic neurons, neuroblasts and NSCs and associates mechanism of neuroprotection in 6-OHDA-induced rat model of PD-like phenotypes. ALCAR (100 mg/kg/day, intraperitoneal (i.p.)) treatment started 3 days prior to 6-OHDA lesioning and continued for another 14 day post-lesioning. We found that ALCAR pretreatment in 6-OHDA-lesioned rats increased expression of neurogenic and the Wnt pathway genes in the striatum and substantia nigra pars compacta (SNpc) region. It suppressed the glial cell activation, improved antioxidant status, increased NSC/neuroblast population and rescued the DAergic neurons in nigrostriatal pathway. ALCAR pretreatment in 6-OHDA-lesioned rats decreased GSK-3β activation and increased nuclear translocation of β-catenin. Functional deficits were restored following ALCAR pretreatment in 6-OHDA-lesioned rats as demonstrated by improved motor coordination and rotational behaviour, confirming protection of DAergic innervations in lesioned striatum. These results indicate that ALCAR exerts neuroprotective effects through the activation of Wnt/β-catenin pathway, suggesting its therapeutic use to treat neurodegenerative diseases by enhancing regenerative capacity.
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Sonu
authors.initials: S
authors.lastname: Singh
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow, 226031, India. shubha_shukla@cdri.res.in.
authors.forename: Shubha
authors.identifier: 0000-0002-2280-5526
authors.initials: S
authors.lastname: Shukla
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001259:Ataxia / Q000150:complications / Q000188:drug therapy; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D009573:Nitrites; D017382:Reactive Oxygen Species; D000108:Acetylcarnitine; D016627:Oxidopamine; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Acetyl-L-carnitine (ALCAR); Neural stem cells; Neuroblasts; Neuroprotection; Oxidative stress; Wnt/β-catenin pathway