Effects of GLT-1 modulator, MC-100093, on neuroinflammatory factor in mesocorticolimbic brain regions of female P rats exposed chronically to ethanol
K.K. Bhowmik1, A. Alotaibi1, M. Abou-Gharbia2, W. Childers2, Y. Sari1
1The University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Pharmacology and Experimental Therapeutics, Toledo, United States, 2Temple University, School of Pharmacy, Pharmaceutical Sciences, Philadelphia, United States
Background: Chronic ethanol intake can elevate extracellular glutamate concentrations in important reward-related brain regions, including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), ultimately resulting in oxidative stress and inflammation.
Aims & Objectives: Recent studies from our laboratory demonstrated that MC-100093, a novel synthetic beta-lactam devoid of antibacterial properties and functioning as a glutamate transporter 1 (GLT-1) modulator, decreased ethanol consumption, and this reduction in ethanol consumption is associated with the normalization of GLT-1 in the NAc.
Method: In this current study, we examined the impact of this GLT-1 modulator, MC-100093, at two doses (100 and 150 mg/kg, i.p.) on chronic ethanol consumption and neuroinflammation in specific subregions of the NAc (core and shell) and mPFC (Prelimbic, PL; and Infralimbic, IL) of female P rats, in a dose-dependent manner.
Results: MC-100093 treatment decreased ethanol consumption at both doses (100 and 150 mg/kg, i.p.) following a five-week drinking paradigm. MC-100093 reduced ethanol-induced elevation of the pro-inflammatory cytokines TNF-α and HMGβ1 across all investigated mesocorticolimbic brain regions. Moreover, MC-100093 treatment attenuated the ethanol-induced elevation of RAGE in these brain regions at both dosages. MC-100093 treatment lowered ethanol consumption, and this behavioral outcome correlated with a reduction in elevated pro-inflammatory markers.
Discussion & Conclusions: These findings are in accordance with previous study reporting that MC-100093 reduced ethanol intake and consequently attenuated ethanol-induced neuroinflammation in male P rats. These data indicate that MC-100093 may serve as a potential therapeutic benefit for reducing the effects of chronic ethanol exposure in male and females.
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