Preclinical reserpine models recapitulating motor and non-motor features of Parkinson’s disease: Roles of epigenetic upregulation of alpha-synuclein and autophagy impairment

Abstract

Reserpine is an effective drug for the clinical treatment of hypertension. It also induces Parkinson’s disease (PD)-like symptoms in humans and animals possible through the inhibition of monoamine vesicular transporters, thus decreasing the levels of monoamine neurotransmitters in the brain. However, the precise mechanisms remain unclear. Herein, we aimed to develop a preclinical reserpine model recapitulating the non-motor and motor symptoms of PD and investigate the underlying potential cellular mechanisms. Incubation of reserpine induced apoptosis, led to the accumulation of intracellular reactive oxygen species (ROS), lowered DNA methylation of alpha-synuclein gene, resulted in alpha-synuclein protein deposition, and elevated the ratio of LC3-II/LC3-Ⅰ and p62 in cultured SH-SY5Y cells. Feeding reserpine dose-dependently shortened the lifespan and caused impairment of motor functions in male and female Drosophila. Moreover, long-term oral administration of reserpine led to multiple motor and non-motor symptoms, including constipation, pain hypersensitivity, olfactory impairment, and depression-like behaviors in mice. The mechanistic studies showed that chronic reserpine exposure caused hypomethylation of the alpha-synuclein gene and up-regulated its expression and elevated the ratio of LC3-II/LC3-Ⅰ and expression of p62 in the substantia nigra of mice. Thus, we established preclinical animal models using reserpine to recapitulate the motor and non-motor symptoms of PD. Chronic reserpine exposure epigenetically elevated the levels of alpha-synuclein expression possible by lowering the DNA methylation status and inducing autophagic impairment in vitro and in vivo.

Autophagy‑regulating miRNAs: Novel therapeutic targets for Parkinson's disease (Review)

“…Recent studies have discovered a downregulation of autophagic components, including Lc3, Beclin-1, p62 and ATG5, in peripheral blood cells of patients with Pd (46,47). Abnormal expression of these autophagy-related proteins in the SN of Pd-related mice is accompanied by both upregulated α-synuclein and clinical symptoms, such as constipation, olfactory impairment and depression-like behaviors (48). Therefore, these findings indicate that autophagy is involved in the pathological process of Pd.…”

Evaluation of the therapeutic potential of cerebrolysin and/or lithium in the male Wistar rat model of Parkinson’s disease induced by reserpine

“…The repeated administration of a low dose of reserpine results in a progressive appearance of motor symptoms in rats which supports the use of reserpine to induce PD animal models (Fernandes et al 2012;Li et al 2022). These motor impairments are accompanied by an enhanced oxidative stress which has been implicated as a possible pathophysiological mechanism in PD (Gaki and Papavassiliou 2014;de Farias et al 2016].…”

“…Recently, Li et al ( 2022 ) demonstrated that reserpine induced motor and non-motor symptoms similar to PD. The authors found that reserpine caused alpha- synuclein deposition, autophagy impairment and tyrosine hydroxylase reduction in the substantia nigra and proposed reserpine model as a valuable tool in PD studies.…”

Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation

“…All data are presented as the mean ± SEM. Data from pramipexole and reserpine treatment in the FST analysis (supplementary data) are the same batch analyzed in our recent study [39]. Differences between two groups were determined with an unpaired twotailed Student's t test.…”