Effects of syringic acid on chronic MPTP/probenecid induced motor dysfunction, dopaminergic markers expression and neuroinflammation in C57BL/6 mice

Abstract

Syringic acid (SA) is a naturally occurring O-methylated trihydroxybenzoic acid present in wine and released as a breakdown product of malvidin, a primary plant pigment (an anthocyanidin). In this study, the neuroprotective efficacy of syringic acid (SA) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probencid (MPTP/p) induced mouse model of PD was investigated. The C57BL/6 mice were given 10 doses of MPTP/p for five consecutive weeks with 3.5 day interval. Administration of MPTP/p led to reduced motor coordination, neurochemicals and tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter-2 (VMAT2) expression. In addition, increased oxidative stress markers and the expression of inflammatory markers, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2). Pre-oral treatment with SA (20 mg/kg) was found to improve the MPTP/p-induced impaired motor functions by restoring the catecholamine content and antioxidant enzymes level. In addition, it ameliorated the expressions of TH, DAT and VMAT2 and also significantly attenuated MPTP/p-induced increased inflammatory markers expressions. These results partially explain the pharmacological efficacy of SA as a potential therapeutic agent for the treatment of MPTP/p-induced mice model of PD, together with its neuroprotective effect and reduce the progression of PD.

Introduction

Parkinson's disease (PD) is a chronic and often devastating, progressive neurodegenerative disease. Loss of dopaminergic neurons in the substantia nigra (SN) leads to the characteristic motor features of tremor, rigidity and bradykinesia, while more widespread neuronal changes lead to complex and variable non-motor symptoms [1]. Strong evidence now exists to support a role of neuroinflammatory events, including oxidative stress [2], impaired mitochondrial function [3] and accumulation of reactive oxygen species (ROS) [4]. The complete mechanisms responsible for nigral dopaminergic cell loss are still obscure.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a well known neurotoxin that produces PD-like symptoms (clinical, biochemical and neurochemical) in humans as well as in animals. It is also being used experimentally to study the idiopathic PD [5], [6]. MPTP induces severe degeneration of dopaminergic neurons in SN when administrated to C57BL/6 mice [7]. Systemic administration of MPTP leads to the conversion of 1-methyl-4-phenylpiridinium (MPP⁺) by the enzyme, monoamine oxidase-B in glial cells [8]. MPP⁺ further enters the dopaminergic neurons with a dopamine transporter (DAT) on the plasma membrane. In the dopaminergic neurons, accumulation of MPP⁺ inhibits mitochondrial respiratory chain complex I further act energy depletion, cellular stress signaling and downstream activation of inflammation [5]. Inflammatory markers, such as tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and cyclooxygenase-2 (COX-2) increase in brains of PD patients [9], [10]. COX-2 has been shown to be one of the earliest markers of oxidative stress and may also contribute to a generalized increase in oxidative stress within its environment [11]. The overproduction of these markers is highly associated with the inflammation and dopaminergic neuronal death [12].

Numerous studies have shown that dietary polyphenols have both in vitro and in vivo neuronal rescuing impact of neurodegenerative diseases to retard or even reverse the accelerated rate of neuronal degeneration [13], [14]. Syringic acid (SA) (4-hydroxy-3,5-dimethoxybenzoic acid) is one of the major benzoic acids and a phenolic compounds derived from edible plants and fruits [15]. Recently, SA has been demonstrated to show strong antioxidant, anti-endotoxic [16], anti-cancer [17] and hepatoprotective activity [18]. Hence, in the present investigation, the effects of SA on the behavioral deficits, oxidative stress and expressions of dopaminergic markers and inflammatory markers expression in a chronic administration of MPTP and probenecid (MPTP/p) induced mice model of PD were examined.