Zonisamide has been proven as an effective
drug for the recovery of degenerating dopaminergic neurons in the animal models of
Parkinson's disease. However, several lines of evidence have questioned the neuroprotective capacity of
zonisamide in animal models of
Parkinson's disease. Although it suppresses dopaminergic neurodegeneration in animal models, the cellular and molecular mechanisms underlying the effectiveness of
zonisamide are not fully understood. The current study demonstrates the effects of
zonisamide on astrocyte cultures and two 6-hydroxydopamine-induced models of
Parkinson's disease. Using primary astrocyte cultures, we showed that
zonisamide up-regulated the expression of
mRNA encoding mesencephalic astrocyte-derived
neurotrophic factor,
vascular endothelial growth factor,
proliferating cell nuclear antigen, metallothionein-2,
copper/
zinc superoxide dismutase, and
manganese superoxide dismutase. Similar responses to
zonisamide were found in substantia nigra where the rats were pre-treated with
6-hydroxydopamine. Notably, pharmacological inhibition of 6-hydroxydopamine-induced toxicity by
zonisamide pre-treatment was also confirmed using rat mesencephalic organotypic slice cultures of substantia nigra. In addition to this,
zonisamide post-treatment also attenuated the nigral
tyrosine hydroxylase-positive neuronal loss induced by
6-hydroxydopamine. Taken together, these studies demonstrate that
zonisamide protected dopamine neurons in two
Parkinson's disease models through a novel mechanism, namely increasing the expression of some important astrocyte-mediated neurotrophic and anti-oxidative factors.