Zonisamide regulates basal ganglia transmission via astroglial kynurenine pathway

Abstract

To clarify the anti-parkinsonian mechanisms of action of zonisamide (ZNS), we determined the effects of ZNS on tripartite synaptic transmission associated with kynurenine (KYN) pathway (KP) in cultured astrocytes, and transmission in both direct and indirect pathways of basal ganglia using microdialysis. Interactions between cytokines [interferon-γ (IFNγ) and tumor-necrosis factor-α (TNFα)] and ZNS on astroglial releases of KP metabolites, KYN, kynurenic-acid (KYNA), xanthurenic-acid (XTRA), cinnabarinic-acid (CNBA) and quinolinic-acid (QUNA), were determined by extreme liquid-chromatography with mass-spectrometry. Interaction among metabotropic glutamate-receptor (mGluR), KP metabolites and ZNS on striato-nigral, striato-pallidal GABAergic and subthalamo-nigral glutamatergic transmission was examined by microdialysis with extreme liquid-chromatography fluorescence resonance-energy transfer detection. Acute and chronic ZNS administration increased astroglial release of KYN, KYNA, XTRA and CNBA, but not QUNA. Chronic IFNγ administration increased the release of KYN, KYNA, CNBA and QUNA, but had minimal inhibitory effect on XTRA release. Chronic TNFα administration increased CNBA and QUNA, but not KYN, KYNA or XTRA. ZNS inhibited IFNγ-induced elevation of KYN, KYNA and QUNA, but enhanced IFNγ-induced that of CNBA. TNFα-induced rises in CNBA and QUNA were inhibited by ZNS. ZNS inhibited striato-nigral GABAergic, striato-pallidal GABAergic and subthalamo-nigral glutamatergic transmission via activation of groups II and III mGluRs. ZNS enhanced astroglial release of endogenous agonists of group II mGluR, XTRA and group III mGluR, CNBA. Activated endogenous mGluR agonists inhibited transmission in direct and indirect pathways of basal ganglia. These mechanisms contribute to effectiveness and well tolerability of ZNS as an adjunct treatment for Parkinson's disease during l-DOPA monotherapy. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Keywords: Astrocyte; Cinnabarinic acid; Kynurenine pathway; Parkinson's disease; Xanthurenic acid; Zonisamide.