title: Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis.
abstract: Neuronal damage in hypoxia and several neurodegenerative disorders is invariably associated with oxidative damage and mitochondrial dysfunction. Administration of acetyl-L-carnitine (ALCAR) on the other hand attenuates neuronal damage, prevents apoptosis, and improves energy status in hypoxic stress through less understood mechanisms. Becasue mitochondrial biogenesis could be a possible mechanism for ALCAR-induced improvement in bioenergetics in neurons, the present study aimed at exploring signaling pathways of ALCAR-induced neuroprotection in hypoxia and possible occurrence of mitochondrial biogenesis. To create global hypoxia, adult Sprague-Dawley rats were exposed to a simulated altitude of 7,620 m at standard temperature and humidity conditions. We here demonstrate that administration of ALCAR to hypoxic rats for a period of 2 weeks effectively protected hippocampal neurons from mitochondrial dysfunction, excitotoxicity, and neurodegeneration. ALCAR administration resulted in peroxisome proliferator-activated receptor γ coactivator-1α and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism. Most notably, calcium buffering into nonfunctional mitochondria ameliorated excitotoxicity and improved bioenergetic status of the hippocampal neurons. Together, the data reveal the immense therapeutic potential of ALCAR for the treatment of ischemia, stroke, and other neurodegenerative disorders associated with hypoxic stress and excitotoxicity.
authors.affiliation: High Altitude Physiology Division, Defence Institute of High Altitude Research, C/o 56 APO, Leh, Jammu and Kashmir, India.
authors.forename: Kalpana Barhwal
authors.initials: KB
authors.lastname: Hota
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Hota
authors.forename: Om Prakash
authors.initials: OP
authors.lastname: Chaurasia
authors.forename: Shashi Bala
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008959:Models, Neurological; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004272:DNA, Mitochondrial; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D034741:RNA, Small Interfering; D000108:Acetylcarnitine; D002118:Calcium