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.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Corroborating our earlier findings, a number of recent studies have highlighted the critical importance of WβC crosstalk with survival and inflammatory pathways in inciting neurogenesis and neurorepair Kalamakis et al, 2019;Kase, Otsu, Shimazaki, & Okano, 2019;Mishra et al, 2019;Morrow & Moore, 2019;Ray et al, 2018;Singh, Mishra, Bharti, et al, 2018b;Singh, Mishra, Mohanbhai, et al, 2018a;Singh, Mishra, & Shukla, 2016).…”

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…3), known as the Ames ALA and ALCAR mixture (AAM), the animals' learning improved and decay of brain mitochondria associated with aging was delayed [Liu et al, 2002a,b;Shenk et al, 2009]. Results from extensive studies by Singh et al [2015] using the 6-OHDA rat model of PD-like phenotype concluded that ALCAR's neuroprotective effects are mediated via activation of the Wnt/b-catenin pathway-suggesting its therapeutic use to treat neurodegenerative diseases by enhancing regenerative capacity [Singh et al, 2015]. In ApoE4 transgenic mice, a model of AD [Laurijssens et al, 2013], AAM enhanced cognitive ability and substantially decreased temporal memory loss [Shenk et al, 2009;Ames, 2010].…”

“…SCFA HDACi have a profound influence on microglial homeostasis [Erny et al, 2015]. Microglia are implicated in several pathways of importance in neurodegenerative disorders, including AD and PD [Asai et al, 2015;Boison and Aronica, 2015;Chung et al, 2015;Jyothi et al, 2015;Li et al, 2015;Singh et al, 2015;Br€ uck et al, 2016;Choong et al, 2016;Olson and Gendelman, 2016;Villegas-Llerena et al, 2016]. They constitute the primary active immune defense in the central nervous system and are constantly scavenging for plaques, damaged neurons, and infectious agents [Estes and McAllister, 2015;Mhatre et al, 2015;Matt and Johnson, 2016].…”

“…Dysregulation of histone H3 is common to both neurodevelopmental and neurodegenerative disorders Singh et al, 2015;Kratsman et al, 2016], and hyperacetylation of histone H3 with HDACi increases expression of Nrf2 [Yu et al, 2010;Prasad, 2015].…”

Downregulation of the Repressor Element 1-Silencing Transcription Factor (REST) Is Associated with Akt-mTOR and Wnt-β-Catenin Signaling in Prion Diseases Models

“…p-GSK3β (Ser9)/total GSK3β protein were significantly decreased, while total GSK3β was increased compared with the normal control ( Figures 4C,D ). β-catenin is a direct substrate of GSK-3β and an intermediate effector of the canonical Wnt signaling pathway (Yost et al, 1996; Singh et al, 2016). GSK-3 activity is also regulated by a wide variety of kinases and systems including the Wnt pathway, Akt, protein kinase A (PKA), protein kinase C (PKC), and MAP kinases (Cross et al, 1995; Chiu and Chuang, 2010).…”