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

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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.

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Abbreviations

PD:

Parkinson’s disease

6-OHDA:

6-Hydroxy dopamine

MDA:

Malondialdehyde

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

MWM:

Morris water maze

OFA:

Open field activity test

MFB:

Medial forebrain bundle

TH:

Tyrosine hydroxylase

DAergic:

Dopaminergic

DRD1:

Dopamine receptor D1

GLT-1:

Glutamate transporter-1

ALCAR:

Acetyl-l-carnitine

VTA:

Ventral tagmental area

SNpc:

Substantia nigra pars compacta

PFC:

Prefrontal cortex

iNOS:

Inducible nitric oxide synthase

GFAP:

Glial fibrillary acidic protein

NeuN:

Neuronal nuclei

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Acknowledgements

This research work was funded by the Council of Scientific and Industrial Research (CSIR) Network grants miND (BSC0115) to Dr. Shubha Shukla. The authors would like to thank the Director of CSIR-Central Drug Research Institute (CDRI), Lucknow, India, for constant support and direction in the study. Sonu Singh and Akanksha Mishra are supported by a research fellowship from the Indian Council of Medical Research (ICMR) and the CSIR, New Delhi, India, respectively. The CSIR-CDRI communication number of this manuscript is 9387.

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Authors and Affiliations

  1. Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Sonu Singh, Akanksha Mishra, Neha Srivastava, Rakesh Shukla & Shubha Shukla

  2. Academy of Scientific and Innovative Research, New Delhi, India

    Akanksha Mishra & Shubha Shukla

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  1. Sonu Singh
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  2. Akanksha Mishra
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  3. Neha Srivastava
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  4. Rakesh Shukla
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  5. Shubha Shukla
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Corresponding author

Correspondence to Shubha Shukla.

Ethics declarations

All animal protocols were approved (approval no. IAEC/2013/51) by our Institutional Animals Ethics Committee (IAEC) following the guidelines of the Committee for the Purpose of Control and Supervision of Experiment on Animals (CPCSEA), which complies with the international norms of Indian National Science Academy (INSA).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Sonu Singh and Akanksha Mishra contributed equally to this work

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Singh, S., Mishra, A., Srivastava, N. et al. Acetyl-l-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats. Mol Neurobiol 55, 583–602 (2018). https://doi.org/10.1007/s12035-016-0293-5

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  • DOI: https://doi.org/10.1007/s12035-016-0293-5

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