Acetyl-l-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats

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...

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Published in:Molecular neurobiology 2018-01, Vol.55 (1), p.583-602
Main Authors: Singh, Sonu, Mishra, Akanksha, Srivastava, Neha, Shukla, Rakesh, Shukla, Shubha
Format: Article
Language:English
Subjects:
6-Hydroxydopamine
Acetyl-L-carnitine
Acetylcarnitine - administration & dosage
Acetylcarnitine - pharmacology
Acetylcarnitine - therapeutic use
Animals
Basal ganglia
Biomedical and Life Sciences
Biomedicine
Carnitine
Cell Biology
Cell Line
Central nervous system diseases
Cognitive ability
Cytokines
Dopamine
Dopamine D1 receptors
Dopamine D2 receptors
Dopaminergic Neurons - drug effects
Dopaminergic Neurons - metabolism
Dopaminergic Neurons - pathology
Excitatory Amino Acid Transporter 2 - metabolism
Gliosis
Gliosis - pathology
Glutamic acid transporter
Glutathione
Glutathione - metabolism
Immune response
Inflammation
Inflammation Mediators - metabolism
Latency
Male
Memory
Memory - drug effects
Microglia
Microglia - drug effects
Microglia - metabolism
Microglia - pathology
Motor Activity - drug effects
Movement disorders
Neurobiology
Neurodegeneration
Neurodegenerative diseases
Neurology
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neuroprotection - drug effects
Neurosciences
Nitric Oxide Synthase Type II - metabolism
Nitric-oxide synthase
Oxidative stress
Oxidative Stress - drug effects
Oxidopamine
Parkinson Disease - drug therapy
Parkinson Disease - pathology
Parkinson Disease - physiopathology
Parkinson's disease
Prefrontal cortex
Rats, Sprague-Dawley
Receptors, Dopamine D1 - metabolism
Rodents
Up-Regulation - drug effects
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Summary: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.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-016-0293-5