Antioxidant‐Mediated Reversal of Oxidative Damage in Mouse Modeling of Complex I Inhibition

Abstract

Mitochondrial dysfunction is a key component of various aging-related pathologies of the brain that result in dementia. As such, it provides an important avenue in development of therapeutic interventions for a host of neurological disorders. A requirement for functional mitochondrial respiratory chain complex I (CI), to accomplish the normal physiological processes regulating memory, seems intuitive. In the present study, a synthetic lipoylcarnitine antioxidant (PMX-500FI; 100 mg/kg/day po) was administered to female ICR mice (3-4-month old) that were subsequently treated with the mitochondrial CI inhibitor, rotenone (400 mg/kg/day). After 1 week, rotenone-induced impairment of neuronal function was evaluated in the hippocampus, a brain region that is involved in regulating memory formation. Electrophysiological recordings in live brain slices showed that long-term potentiation (LTP) was reduced by rotenone exposure (P < 0.05) while pretreatment with PMX-500FI maintained LTP similar to control levels (P > 0.05). Potentiation during theta burst stimulation (TBS) was similar among treatment groups (P > 0.05); however, neurotransmitter release, which increased in control mice after TBS, was lower in rotenone treated mice (P < 0.05), and was accompanied by reduced basal synaptic transmission (P < 0.05), increased proapoptotic signaling and decreased extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation (P < 0.05). For each of these determinations, pretreatment with PMX-500FI alleviated the harmful effects of rotenone. These results illustrate that treatment with antioxidant PMX-500FI is protective against rotenone-induced impairment of neuronal bioenergetics in the mouse hippocampus, in regard to both excitatory synaptic physiology and proapoptotic signaling. The protective effect of PMX-500FI against rotenone-induced disruption of cellular bioenergetics may have important therapeutic implications for treating aging-related dementia and other diseases related to mitochondrial dysfunction and/or oxidative damage.

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].…”

“…An optimal balance of BCL2 family proteins is essential in ensuring cell survival [Dixit et al, 2015;Denzer et al, 2016]. Parameshwaran et al [2015] showed that when mice were exposed to rotenone, the induced changes in increased BAX translocation to mitochondria and decreased phospho BCL-associated agonist of cell death were ameliorated by PMX-500FI.…”

“…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. Treatment with PMX-500FI also prevented rotenoneinduced decline in presynaptic release and basal synaptic transmission [Parameshwaran et al, 2015]. Mitochondrial apoptotic priming [Gibson and Davids, 2015] is a critical factor in determining whether or not a stressed-cell will undergo apoptosis [for review see Sarosiek et al, 2013].…”

“…The carnitinoids PMX-500FI, PMX500DBr, PMX-550B, and PMX-550DBr overcome these deficiencies. They cross the blood-brain-barrier, are actively transported into cells and accumulate inside the mitochondrial matrix, and, importantly, are able to accumulate in the nucleus of cells harboring impaired mitochondria, where they can act as HDACi [Donohoe et al, 2012] to upregulate the proapoptotic protein, BAX [Dmitriev and Papkovsky, 2015;Parameshwaran et al, 2015;Salama et al, 2015;Vahid et al, 2015], and the Nrf2 pathway [Fern andez-Galilea et al, 2015]. Thus, these compounds have therapeutic potential for treating a wide range of neurological disorders, as well as mitochondrial diseases and syndromes, including GWI, all of which share mitochondrial dysfunction in their etiology [Wallace, 2013;Nicolson et al, 2014;Pagano et al, 2014;Pickrell and Youle, 2015 …”

Bioprotective Carnitinoids: Lipoic Acid, Butyrate, and Mitochondria‐Targeting to Treat Radiation Injury: Mitochondrial Drugs Come of Age

“…In support of this concept, preliminary results from ongoing studies [Parameshwaran et al, ] show that PMX‐500FI can protect against neuromotor decline in vivo and restore deficits in long‐term potentiation (LTP) induced by rotenone exposure in mice. Thus, as demonstrated in Parameshwaran et al [], PMX‐500FI: Neutralizes synaptic LTP deficits, as evidenced by effects on field excitatory postsynaptic potentials (fEPSP) recorded following theta burst stimulation (Fig. ). Prevents declines in presynaptic release and basal synaptic transmission, also measured by effects on fEPSP amplitudes. Ameliorates declines in basal synaptic transmission, as shown by increased BAX protein translocation to mitochondria and decreases phosphorylated BCL‐associated agonist of cell death (BAD), as determined by western blot analysis. Inhibits decreases in phosphorylation of extracellular signal‐related kinase 1/2 (ERK1/2), as determined by western blot analysis. …”