Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)neurotoxicity in mice

Abstract

We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.

Zonisamide Treatment Delays Motor Neuron Degeneration and Astrocyte Proliferation in Wobbler Mice

“…Intraperitoneal administration of ZNS (40 mg/kg/day for 7 days) protected dopaminergic neurons in the substantia nigra of MPTP-mice, and also inhibited proliferation of GFAPimmunoreactive astrocytes and microglia in the substantia nigra [6]. This drug rescued dopaminergic neurons and enhanced the number of S100b-immunoreactive astrocytes in 6-hydroxydopamine-injected hemiparkinsonian mice [18].…”

“…ZNS was reported to have benefi ts in several experimental animal models [7], including epileptic seizure [15,16], brain ischemia [4,17] and Parkinson's disease [6,18,19]. Intraperitoneal administration of ZNS (40 mg/kg/day for 7 days) protected dopaminergic neurons in the substantia nigra of MPTP-mice, and also inhibited proliferation of GFAPimmunoreactive astrocytes and microglia in the substantia nigra [6].…”

“…In addition to the anti-convulsant properties, ZNS reduced neonatal hypoxic-ischemic damage in experimental animals [4]. This ant-epileptic drug prevented against dopamine quinone formation induced by excess amount of cytosolic dopamine outside the synaptic vesicles [5] and also attenuated loss of dopaminergic neurons after 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mice [6] Therefore, ZNS had multifunctional effects on several kinds of neurons [7]. However, little is known about a neuroprotective potential of ZNS on damaged motor neurons.…”

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.…”

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry

“…In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease in mice, zonisamide has a neuroprotective effect inhibiting the proliferation of microglia in the striatum and substantia nigra [144]. Pregabalin improves motor function recovery after spinal cord injury in rats, possibly via the neuroprotective effect of suppressing microglial activation and oligodendrocyte apoptosis [145].…”