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Neurorestorative effects of sub-chronic administration of ambroxol in rodent model of Parkinson’s disease

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Abstract

Disease-modifying agents are unmet medical need for Parkinson’s disease (PD). Drugs are under clinical trial to halt its progression, such as ambroxol due to its glucocerebrosidase (GCase)-stimulating activity. However, the neurorestorative effect of ambroxol is not yet investigated in any of the well-established PD models in vivo. Ambroxol was administered as 400 mg/kg orally twice a day from D-28 to D-70 after the unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in male rats. Behavioral parameters were observed every week, and at last, tyrosine hydroxylase (TH), dopamine transporter (DAT), glucocerbrosidase (GCase) enzymatic and mitochondrial complex-I activity, α-synuclein levels, and Nissl’s staining were performed. Behavioral functions were progressively recovered. Ambroxol restored TH and DAT levels on D-71 as the markers of dopaminergic cell and extracellular DA concentration respectively, indicating the recovery of dopaminergic system. Factors involved in PD pathogenesis such as GCase enzymatic and mitochondrial complex-I activity were restored, and α-synuclein pathology was decreased by ambroxol. GCase deficiency is involved in mitochondrial impairment and formation of oligomeric α-synuclein aggregates which negatively affect mitochondrial function. Nissl bodies were also normalized. Therefore, both the GCase-stimulating and α-synuclein pathology-diminishing effects of ambroxol may be responsible for increment in mitochondrial function and restoration of dopaminergic system. These may act as significant mechanisms for disease-modifying potential of ambroxol. The current study provides the preclinical evidence to support the neurorestorative potential of ambroxol in 6-OHDA-induced hemiparkinson’s rat model and indicates its possible use as disease-modifying agent in PD.

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Acknowledgements

The authors wish to acknowledge Merril Pharma Pvt. Ltd., Roorkee for providing ambroxol hydrochloride (active pharmaceutical ingredient) as a gift sample. This work was supported by the teaching assistantship to Akanksha Mishra from Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, U.P., India.

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The research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, U.P., 221005, India

    Akanksha Mishra & Sairam Krishnamurthy

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The conception and design of study was done by AM and SK. AM acquired the data, which was analyzed and interpreted by AM and SK. AM and SK drafted the article and revised it for important intellectual content. SK approved the final version to be submitted.

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Correspondence to Sairam Krishnamurthy.

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All the experimental protocols were approved by institutional animal ethical committee, Banaras Hindu University (Dean/2016/CAEC/33).

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The authors declare that they have no conflict of interest.

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All the experiments were performed in line with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978). All the experimental protocols were approved by Institutional animal ethical committee, Banaras Hindu University (Dean/2016/CAEC/33). This article does not contain any studies with human participants performed by any of the authors.

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Mishra, A., Krishnamurthy, S. Neurorestorative effects of sub-chronic administration of ambroxol in rodent model of Parkinson’s disease. Naunyn-Schmiedeberg's Arch Pharmacol 393, 429–444 (2020). https://doi.org/10.1007/s00210-019-01737-9

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