title: Alpha-lipoic acid-mediated activation of muscarinic receptors improves hippocampus- and amygdala-dependent memory.
abstract: Aluminum (Al) is a neurotoxic agent which readily crosses the blood-brain-barrier (BBB) and accumulates in the brain leading to neurodegenerative disorders, characterised by cognitive impairment. Alpha-lipoic acid (ALA) is an antioxidant and has a potential to improve cognitive functions. This study aimed to evaluate the neuroprotective effect of ALA in AlCl3-induced neurotoxicity mouse model. Effect of ALA (25mg/kg/day) was evaluated in the AlCl3-induced neurotoxicity (AlCl3 150 mg/kg/day) mouse model on learning and memory using behaviour tests and on the expression of muscarinic receptor genes (using RT-PCR), in hippocampus and amygdala. Following ALA treatment, the expression of muscarinic receptor genes M1, M2 and choline acetyltransferase (ChaT) were significantly improved (p<0.05) relative to AlCl3-treated group. ALA enhanced fear memory (p<0.01) and social novelty preference (p<0.001) comparative to the AlCl3-treated group. Fear extinction memory was remarkably restored (p<0.001) in ALA-treated group demonstrated by reduced freezing response as compared to the AlCl3-treated group which showed higher freezing. In-silico analysis showed that racemic mixture of ALA has higher binding affinity for M1 and M2 compared to acetylcholine. These novel findings highlight the potential role of ALA in cognitive functions and cholinergic system enhancement thus presenting it an enviable therapeutic candidate for the treatment of neurodegenerative disorders.
authors.affiliation: Neurobiology Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
authors.forename: Aamra
authors.initials: A
authors.lastname: Mahboob
authors.affiliation: Neurobiology Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
authors.forename: Syeda Mehpara
authors.initials: SM
authors.lastname: Farhat
authors.affiliation: Neurobiology Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
authors.forename: Ghazala
authors.initials: G
authors.lastname: Iqbal
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
authors.forename: Mustafeez Mujtaba
authors.initials: MM
authors.lastname: Babar
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
authors.forename: Najam-us-Sahar Sadaf
authors.initials: NU
authors.lastname: Zaidi
authors.affiliation: Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Nabavi
authors.affiliation: Neurobiology Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan. Electronic address: touqeer.aahmed@gmail.com.
authors.forename: Touqeer
authors.initials: T
authors.lastname: Ahmed
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000633:toxicity; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002712:Chlorides / Q000633:toxicity; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D018696:Neuroprotective Agents / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D008063:Thioctic Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017607:Aluminum Compounds; D002712:Chlorides; D018696:Neuroprotective Agents; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D000077410:Aluminum Chloride; D008063:Thioctic Acid; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D000109:Acetylcholine
keywords: Alpha-lipoic acid; Amygdala; Choline acetyltransferase; Cholinergic receptors; Hippocampus; Memory