Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction

Abstract

Growing evidence from in vitro studies supports that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, has neuroprotective effects. The present study investigated whether VPA reduces brain damage and improves functional outcome in a transient focal cerebral ischemia model of rats. Subcutaneous injection of VPA (300 mg/kg) immediately after ischemia followed by repeated injections every 12 h, was found to markedly decrease infarct size and reduce ischemiainduced neurological deficit scores measured at 24 and 48 h after ischemic onset. VPA treatment also suppressed ischemia-induced neuronal caspase-3 activation in the cerebral cortex. VPA treatments resulted in a time-dependent increase in acetylated histone H3 levels in the cortex and striatum of both ipsilateral and contralateral brain hemispheres of middle cerebral artery occlusion (MCAO) rats, as well as in these brain areas of normal, non-surgical rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC) inhibitor. Similarly, heat shock protein 70 (HSP70) levels were timedependently up-regulated by VPA in the cortex and striatum of both ipsilateral and contralateral sides of MCAO rats and in these brain areas of normal rats. Altogether, our results demonstrate that VPA is neuroprotective in the cerebral ischemia model and suggest that the protection mechanisms may involve HDAC inhibition and HSP induction. Keywords: acetylated histone 3, cerebral ischemia, heat shock protein 70, neuroprotection, rat, valproic acid. (De Sarno et al. 2002). In rat cortical neurons, long-term VPA treatment blocks glutamate-induced excitotoxicity (Hashimoto et al. 2002) and prolongs life span of these cortical cultures (Jeong et al. 2003). Similar to the effect of another mood stabilizing drug, lithium, VPA protects mature rat cerebellar granule cells in cultures from NMDA receptor-mediated excitotoxicity and this action is mimicked by other histone HDAC inhibitors such as butyrate and trichostatin A (Kanai et al. 2002). A growing body of reports also demonstrate that VPA is neuroprotective against a variety of other insults (Mark et al. 1995;Mora et al. 1999;Bown et al. 2000;Wang et al. 2003).Stroke is one of the leading causes of mortality and morbidity world-wide. Although our knowledge concerning the molecular and cellular pathophysiology of brain injury after focal ischemia has advanced greatly, the development of new treatment drugs for acute ischemic stroke has not progressed as rapidly. The use of intravenous recombinant Abbreviations used: HDAC, histone deacetylase; HSP70, heat shock protein 70; GSK-3b, glycogen synthase kinase-3b; MCAO, middle cerebral artery occlusion; rt-PA, recombinant tissue-type plasminogen activator; TTC, 2,3,5-triphenyltetrazolium chloride; VPA, valproic acid.

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…It is possible that the therapeutic effects of valproate may in part be related to this important epigenetic mechanism. In support of this, valproate and several other HDAC inhibitors have shown neuroprotective effects in animal models of cerebral ischemia, 190,191 Parkinson's disease, 192 and Huntington's disease. 193,194 Weaver and associates 195 demonstrated in rat pups that behaviorally programmed, persistent epigenomic alterations of a glucocorticoid receptor gene promoter in the hippocampus induced by certain styles of maternal behavior could be reversed by central infusion of an HDAC inhibitor.…”

Epigenetic Mechanisms in Cerebral Ischemia

“…47) with its downstream actors BCL-2-associated X protein (BAX) 104 and caspase 3 (ref. 49) can be detected. Further, agents that are a typical for endoplasmatic reticulum stress induced cell death, like C/EBP homology protein (CHOP) and caspase 12 (ref.…”

“…In and around the ischemic core, a general decrease of histone H3 acetylation [46][47][48][49][50] as well as of H4 acetylation levels [51][52][53][54] was identified in multiple studies. Vast deacetylation processes occur quickly upon an ischemic insult and induce a fatal course of events.…”

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

“…2 Valproic acid as well as lithium have shown protective effects on neural tissue in vivo and in vitro. [3][4][5][6] Both medications have also been found to regulate biochemical processes involved in cellular protection. 7,8 Furthermore, in vivo magnetic resonance spectroscopy (MRS) of the brain has provided evidence for a neurotrophic/neuroprotective effect of lithium in patients.…”