Neuroprotective effects of the mood stabilizer lamotrigine against glutamate excitotoxicity: roles of chromatin remodelling and Bcl-2 induction

Abstract

Lamotrigine (LTG), a phenyltriazine derivative and anti-epileptic drug, has emerged as an effective first-line treatment for bipolar mood disorder. Like the other mood stabilizers lithium and valproate, LTG also has neuroprotective properties but its exact mechanisms remain poorly defined. The present study utilized rat cerebellar granule cells (CGCs) to examine the neuroprotective effects of LTG against glutamate-induced excitotoxicity and to investigate potential underlying mechanisms. CGCs pretreated with LTG were challenged with an excitotoxic dose of glutamate. Pretreatment caused a time- and concentration-dependent inhibition of glutamate excitotoxicity with nearly full protection at higher doses (≥ 100 μm), as revealed by cell viability assays and morphology. LTG treatment increased levels of acetylated histone H3 and H4 as well as dose- and time-dependently enhanced B-cell lymphoma-2 (Bcl-2) mRNA and protein levels; these changes were associated with up-regulation of the histone acetylation and activity of the Bcl-2 promoter. Importantly, lentiviral-mediated Bcl-2 silencing by shRNA reduced both LTG-induced Bcl-2 mRNA up-regulation and neuroprotection against glutamate excitotoxicity. Finally, the co-presence of a sub-effective concentration of LTG (10 μm) with lithium or valproate produced synergistic neuroprotection. Together, our results demonstrate that the neuroprotective effects of LTG against glutamate excitotoxicity likely involve histone deacetylase inhibition and downstream up-regulation of anti-apoptotic protein Bcl-2. These underlying mechanisms may contribute to the clinical efficacy of LTG in treating bipolar disorder and warrant further investigation.

Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission

“…Lithium, valproate and lamotrigine are enhancers of neurogenesis (Manji et al, 2000;Leng et al, 2013) and are also investigated in various models of Table 3 Effect of chronic treatment with perampanel on the number of c-Fos proteinpositive cells/0.1 mm 2 in different brain regions of Gria1 À / À and WT animals.…”

Understanding the molecular mechanisms underlying mood stabilizer treatments in bipolar disorder: Potential involvement of epigenetics

“…However, lithium administration was able to disrupt rotenone's epigenetic actions without affecting DNMT and TET activity [65]. Another study showed that lamotrigine protected neurons against excitoxicity in rat cerebellar granule cells [67]. This action was hypothesized to be mediated by a moderate increase in histone acetylation.…”

“…This hypothesis was further supported by a slight attenuation of HDAC caused by lamotrigine. The antiapoptotic effects of lamotrigine seemed to result from increased acetylation of B-Cell CLL/Lymphoma 2 (bcl-2) promoter and subsequent upregulation [67]. As far as VPA is concerned, neuroprotective actions were accompanied by H3 hyperacetylation in a series of induced-neurotoxicity cell models [57,[68][69][70].…”

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Likewise, identification of VPA as a class I and IIa HDAC inhibitor (Gottlicher et al, 2001;Phiel et al, 2001) suggests that associated reversion of HDACdependent transcriptional rep ression and histone hyperacetylation could be involved in its mood-stabilizing properties (Gavin and Sharma, 2010;Machado-Vieira et al, 2011). Less studied are the mechanisms of action of LTG and CBZ; neuroprotective effects of LTG exerted through upregulation of excitatory amino acid transporter activity (Schloesser et al, 2012;Leng et al, 2013) and increased global DNA methylation induced by CBZ (Pisanu et al, 2018) are the best described epigenetic changes. The histone deacetylase inhibitory properties of anticonvulsants (Eyal et al, 2004) and the potent antioxidant effects of lithium (Leng et al, 2008;Dwivedi and Zhang, 2015) have been postulated as potential pathways to reverse dysfunctional epigenetic regulation and variability in treatment response (Machado-Vieira et al, 2011).…”