ORIGINAL ARTICLE Neurorestorative effects of sub-chronic administration of ambroxol in rodent model of Parkinson’s disease Akanksha Mishra 1 & Sairam Krishnamurthy 1 Received: 14 June 2019 /Accepted: 20 September 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 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 mitochon- drial 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. Keywords Ambroxol . Neurorestoration . 6-Hydroxydopamine . Parkinson’ s disease . Glucocerebrosidase . Disease-modifying agent Introduction Disease-modifying medications are unmet medical require- ment in the treatment of neurodegenerative disorders (Francardo et al. 2017; Reidling et al. 2018). Disease modifi- cation may be achieved by either restraining the primary events leading to neurodegeneration, namely Bneuroprotection,^ or upgrading the regenerative and com- pensatory phenomena in the related brain region; the process is defined as Bneurorestoration^ (Francardo et al. 2017). Parkinson’ s disease (PD), one of the neurodegenerative chronic disorders, affects approximately 0.4–1% of people around 60–79 years of age and 1.9% of people more than 80 years of age worldwide (Pringsheim et al. 2014). All the marketed drugs for PD can only delay severe motor symptoms in patients and improve their overall quality of life (Pires et al. 2017). Levodopa in combination with dopamine decarboxyl- ase inhibitor is used for symptomatic treatment of PD (Müller 2012). However, neurorestoration which can cure PD is still under investigation (Francardo et al. 2017). PD is mostly a sporadic disorder and its etiology is not completely known. However, the study of genetics, epidemiology, and neuropa- thology provided new insights into the underlying mecha- nisms of PD (Moore et al. 2005). Apart from dopamine deficit in the nigrostriatal tract α-synuclein, mitochondrial dysfunc- tion, oxidative stress, and glucocerebrosidase (GCase) defi- ciency are some of the other factors reported to be involved in PD pathogenesis (Moore et al. 2005; Gegg et al. 2012). * Sairam Krishnamurthy ksairam.phe@iitbhu.ac.in; saibliss@hotmail.com 1 Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, U.P. 221005, India Naunyn-Schmiedeberg's Archives of Pharmacology https://doi.org/10.1007/s00210-019-01737-9