Tetramethylpyrazine Ameliorates Rotenone-Induced Parkinson's Disease in Rats: Involvement of Its Anti-Inflammatory and Anti-Apoptotic Actions

Abstract

Parkinson's disease (PD) is a slowly progressive neurodegenerative movement disorder. Apoptosis, neuroinflammation, and oxidative stress are the current hypothesized mechanisms for PD pathogenesis. Tetramethylpyrazine (TMP), the major bioactive component of Ligusticum wallichii Franchat (ChuanXiong), Family Apiaceae, reportedly has anti-apoptotic, anti-inflammatory and antioxidant effects. This study investigated the role of 'TMP' in preventing rotenone-induced neurobiological and behavioral sequelae. A preliminary dose-response study was conducted where rats received TMP (10, 20, and 40 mg/kg, i.p.) concomitantly with rotenone (2 mg/kg, s.c.) for 4 weeks. Catalepsy, locomotor activity, striatal dopamine content, and tyrosine hydroxylase "TH" and α-synuclein immunoreactivity were evaluated. The selected TMP dose (20 mg/kg) was used for western blot analysis of Bax, Bcl2, and DJ-1, immunohistochemical detection of nuclear factor kappa B (NF-кB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and glial fibrillary acidic protein (GFAP) expression, in addition to biochemical analysis of caspase-3 activity, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) levels. Results showed that TMP (20 mg/kg) significantly improved midbrain and striatal TH expression and striatal dopamine content as well as the motor deficits, compared to rotenone-treated group. These results were correlated with reduction in caspase-3 activity and α-synuclein expression, along with improvement of midbrain and striatal Bax/Bcl2 ratio compared to rotenone-treated group. TMP also attenuated rotenone-induced upregulation of Nrf2/HO-1 pathway. Furthermore, TMP downregulated rotenone-induced neuroinflammation markers: NF-кB, iNOS, COX2, and GFAP expression in both the midbrain and striatum. Taken together, the current study suggests that TMP is entitled to, at least partially, preventing PD neurobiological and behavioral deficits by virtue of its anti-apoptotic, anti-inflammatory, and antioxidant actions.