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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.
Mol Neurobiol. 2016 Sep; 53(7):4286-301.MN

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+Show Affiliations

Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow, 226031, India.Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow, 226031, India.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26223802

Citation

Singh, Sonu, et al. "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." Molecular Neurobiology, vol. 53, no. 7, 2016, pp. 4286-301.
Singh S, Mishra A, Shukla S. 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. Mol Neurobiol. 2016;53(7):4286-301.
Singh, S., Mishra, A., & Shukla, S. (2016). 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. Molecular Neurobiology, 53(7), 4286-301. https://doi.org/10.1007/s12035-015-9361-5
Singh S, Mishra A, Shukla S. 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. Mol Neurobiol. 2016;53(7):4286-301. PubMed PMID: 26223802.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Singh,Sonu, AU - Mishra,Akanksha, AU - Shukla,Shubha, Y1 - 2015/07/30/ PY - 2015/6/8/received PY - 2015/7/13/accepted PY - 2015/7/31/entrez PY - 2015/8/1/pubmed PY - 2018/1/9/medline KW - Acetyl-L-carnitine (ALCAR) KW - Neural stem cells KW - Neuroblasts KW - Neuroprotection KW - Oxidative stress KW - Wnt/β-catenin pathway SP - 4286 EP - 301 JF - Molecular neurobiology JO - Mol Neurobiol VL - 53 IS - 7 N2 - 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. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/26223802/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_ DB - PRIME DP - Unbound Medicine ER -