A Novel Anti-Parkinsonian Agent, Zonisamide, Attenuates MPTP-Induced Neurotoxicity in Mice

Abstract

Zonisamide, an anti-convulsant drug, has recently been shown to exert beneficial effects in Parkinson's disease (PD). However, actual pathophysiological mechanism underlying the anti-parkinsonian effect of zonisamide remains uncertain. Here we tested exactly the neuroprotective effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. We observed that zonisamide attenuated MPTP-induced dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) depletion in the striatum and reduced the loss of tyrosine hidroxylase (TH) positive neurons and the increase of glial fibrillary acidic protein (GFAP) positive astrocytes in the striatum and substantia nigra after 5 days. Our Western blot analysis study also showed that zonisamide can prevent the decrease of TH protein levels and increase of GFAP protein levels in the striatum 5 days after MPTP treatment. In the present study, on the other hand, zonisaimde treatment showed no significant changes of the striatal dopamine, DOPAC, and HVA content in the striatum of normal mice after 1 day, as compared to the vehicle-treated group. Furthermore, zonisamide produced a significant increase of the TH protein levels in the striatum after 1 day, as compared to vehicle-treated group. In contrast, zonisamide showed no significant changes of the GFAP protein levels in the striatum after 1 day, as compared to vehicle-treated group. These results show that anticonvulsant drug, zonisamide, has the neuroprotective effect in the MPTP model of PD in mice. Our study also demonstrates that the neuroprotective effect of zonisamide against dopaminergic cell damage may be mediated by the elevation of TH activity on dopaminergic system after MPTP treatment in mice. Our findings suggest that zonisamide may offer a new approach for the treatment of PD.

Changes of gene expression profiles in the cervical spinal cord by acupuncture in an MPTP-intoxicated mouse model: Microarray analysis

“…It was especially reported that MPTP induces the degeneration of spinal cord in a mouse model of MPTP intoxication (Samantaray et al, 2008). Pharmaceutical studies have been conducted using these animal models of PD-like neuropathological features as well as using actual PD patients (Dutta et al, 2008;Etminan et al, 2003;Hamaue 2000;Kasture et al, 2009;Liang et al, 2007;Neef and van Laar, 1999;Yano et al, 2009). However, these studies have not yet led to the development of satisfactory anti-parkinsonism drugs with longterm therapeutic effects for PD patients; for example, long-term treatment with Levodopa (a drug used to treat PD) is known to cause serious side effects such as dyskinesia (Calon et al, 2000).…”

Influence of Zonisamide on the LTP-like Effect Induced by Quadripulse Transcranial Magnetic Stimulation (QPS)

“…The dopaminergic mechanisms are dopamine release induction [14,15] and MAO-B inhibition [16]. The non-dopaminergic mechanisms are calcium channel blocker [13] glutamate [17], GABA [18] modulation, and so on.…”

Zonisamide Attenuates α-Synuclein Neurotoxicity by an Aggregation-Independent Mechanism in a Rat Model of Familial Parkinson’s Disease

“…An earlier article reported that acute administration of ZNS (20 and 50 mg/kg) in rats increased intracellular and extracellular levels of dopamine and its metabolites in the striatum through inhibition of monoamine oxidase type B (MAO-B) activity [9]. Alternatively, ZNS has been reported to increase the activity and expression of tyrosine hydroxylase (TH) [10], and stimulate dopamine release in the rat striatum [9]. ZNS may improve motor impairments of Parkinson’s disease by its multiple effects on dopamine release and synthesis [11].…”

“…Furthermore, experiments using neurotoxin-based mouse models have provided insights into the protective effects of ZNS against neuronal death. In MPTP-treated mice, intraperitoneal administration of ZNS (20 mg/kg) mitigated loss of nigral TH-positive neurons with attenuating dopamine depletion in the striatum [10]. In mice that received 6-OHDA to induce hemiparkinsonism, repeated intraperitoneal injection of ZNS (30 mg/kg) for 7 days also abrogated the reduction in nigral dopamine neurons [12].…”