title: Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.
abstract: Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in neurodegenerative diseases.
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.|Academy of Scientific and Innovative Research, New Delhi, 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.
authors.forename: Neha
authors.initials: N
authors.lastname: Srivastava
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: Rakesh
authors.initials: R
authors.lastname: Shukla
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.|Academy of Scientific and Innovative Research, New Delhi, 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 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018836:Inflammation Mediators; D017447:Receptors, Dopamine D1; C493395:Slc1a2 protein, rat; D000108:Acetylcarnitine; D016627:Oxidopamine; D052247:Nitric Oxide Synthase Type II; D005978:Glutathione
keywords: Acetyl-L-carnitine; Dopamine receptor; Glutamate transporter-1; Mesocorticolimbic pathway; Microglial activation; Neuronal survival