Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia

Abstract

Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia.

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…It is postulated that the antioxidant and antiinflammatory properties of AAM are the most important attributes of this compound [Hnia et al, 2007;Maczurek et al, 2008;Shenk et al, 2009;Mecocci and Polidori, 2012;Sozio et al, 2013;Salminen et al, 2014]. In addition, data from our labs Parameshwaran et al, 2015;Moos et al, 2016] and other studies [Karagiannis and Maulik, 2012;Karagiannis and Ververis, 2012] suggest epigenetic chromatin remodeling may also be involved [Aydin et al, 2012;Jakovcevski and Akbarian, 2012;Lunnon and Mill, 2013;Millan, 2013].…”

“…They constitute the primary active immune defense in the central nervous system and are constantly scavenging for plaques, damaged neurons, and infectious agents [Estes and McAllister, 2015;Mhatre et al, 2015;Matt and Johnson, 2016]. Butyrate is the most potent of the SCFA HDACi Wagner et al, 2013;Natarajan and Pluznick, 2014], and its potential use in the intervention of neurodegenerative diseases and psychiatric disorders is of longstanding interest [Chuang et al, 2009;Thomas, 2009;Grayson et al, 2010;Canani et al, 2012;Harrison and Dexter, 2013;Rosenstock, 2013;De Vadder et al, 2014;Sezgin and Dincer, 2014;Szyf, 2015;Volmar and Wahlestedt, 2015;Moos et al, 2016].…”

“…4), are actively transported and mitochondria-localizing biomimetic CoA surrogates of SCFAs [US Patents 6,316,652 and 8,741,853;Steliou et al, 2009Steliou et al, , 2012Steliou et al, , 2015Moos et al, 2016]. Mitochondria-targeting molecules attached to a triphenylphosphonium (TPP) cation also localize (by Coulombic pressure) in mitochondria, for example, the lipoic acid derivative, MitoL (Fig.…”

“…Long-term potentiation (LTP) represents an enduring form of synaptic plasticity, which is critical to the process of learning and memory retention [Forsyth et al, 2015;Moos et al, 2016]. Studies by Parameshwaran et al [2010] showed lipoyl-L-carnitine, PMX-500FI, protected against neuromotor decline in vivo, and reversed rotenone-induced reductions in LTP in the mouse Schaffer collateral-CA1 synapses [Irwin et al, 2013;Parameshwaran et al, 2012Parameshwaran et al, , 2015.…”

“…An emerging and promising approach to treating these diseases leverages their sensitivity to activation of the master regulator of antioxidant and cytoprotective genes and their products, namely, nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Nrf2/ARE), and mitophagy [Osborne et al, 2014;Pagano et al, 2014;Palikaras and Tavernarakis, 2014;Johnson and Johnson, 2015;Joshi et al, 2015;Matic et al, 2015;Nikoletopoulou et al, 2015;Prasad, 2015;Rai et al, 2015;Denzer et al, 2016;Moos et al, 2016;Suliman and Piantadosi, 2016].…”