Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of gamma-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients.

Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

“…The epigenetic influence of HDIs on gene expression make them a useful new class of pharmacological agents that could ameliorate various disease conditions. For example, HDIs also promote neuronal survival in ischemic injury, [14][15][16][17] multiple sclerosis [18,19], and Alzheimer's and Huntington's disease models [20][21][22][23][24]. These multiple roles of HDIs can be attributed to alterations in the expression of different gene sets by increasing acetylation of chromatin.…”

Valproic acid decreases cell proliferation and migration in the cerebellum of zebrafish larvae

“…This compound is one of the major drugs administered to suppress seizures in humans and a variety of animal models (Gobbi & Janiri 2006;Jessberger et al 2007). VPA is also used to treat bipolar disorders, social phobia, neuropathic pain (Winterer & Hermann 2000;Hosák & Libiger 2002;Smith et al 2010), and neurodegenerative disorders such as Huntington's disease and Alzheimer's disease (Ren et al 2004;Qing et al 2008;Zádori et al 2009). However, VPA exposure during the prenatal and postnatal periods is also known to have severe negative effects on the brain and behavior at later adult stages.…”

Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro

“…Furthermore, transplantation of neural stem cells together with administration of VPA dramatically enhanced the restoration of hind limb function of SCI mice (Abematsu et al, 2010). Besides spinal cord injury, VPA exerts protective effects for various neurological diseases, including SCI, stroke, traumatic brain injury, motor neuron diseases, Parkinson’s disease, Alzheimer’s disease and Huntington’s disease (Brichta et al, 2006; Dash et al, 2010; Kidd and Schneider, 2011; Qing et al, 2008; Ren et al, 2004; Rouaux et al, 2007; Sinn et al, 2007; Zadori et al, 2009). There is now accumulating evidence that VPA may have potential in the treatment of central nervous system (CNS) disorders and the neuroprotective functions are linking with its inhibition on histone deacetylases (HDACs) (Nalivaeva et al, 2009).…”