Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.

Kolaviron is a phytochemical isolated from Garcina kola (G. kola); a common oral masticatory agent in Nigeria (West Africa). It is a bioflavonoid used--as an antiviral, anti-inflammatory and antioxidant--in relieving the symptoms of several diseases and infections. In this study we have evaluated the neuroprotective and regenerative effect of kolaviron in neurons of the prefrontal cortex (Pfc) before or after exposure to sodium azide (NaN3) induced oxidative stress. Separate groups of animals were treated as follows; kolaviron (200 mg/Kg) for 21 days; kolaviron (200 mg/Kg for 21 days) followed by NaN3 treatment (20 mg/Kg for 5 days); NaN3 treatment (20 mg/Kg for 5 days) followed by kolaviron (200 mg/Kg for 21 days); 1 ml of corn-oil (21 days-vehicle); NaN3 treatment (20 mg/Kg for 5 days). Exploratory activity associated with Pfc function was assessed in the open field test (OFT) following which the microscopic anatomy of the prefrontal cortex was examined in histology (Haematoxylin and Eosin) and antigen retrieval Immunohistochemistry to show astroglia activation (GFAP), neuronal metabolism (NSE), cytoskeleton (NF) and cell cycle dysregulation (p53). Subsequently, we quantified the level of Glucose-6-phosphate dehydrogenase (G6PDH) and lactate dehydrogenase (LDH) in the brain tissue homogenate as a measure of stress-related glucose metabolism. Kolaviron (Kv) and Kolaviron/NaN3 treatment caused no prominent change in astroglia density and size while NaN3 and NaN3/Kv induced astroglia activation and scar formation (astrogliosis) in the Pfc when compared with the control. Similarly, Kolaviron and Kv/NaN3 did not alter NSE expression (glucose metabolism) while NaN3 and NaN3/Kv treatment increased cortical NSE expression; thus indicating stress related metabolism. Further studies on enzymes of glucose metabolism (G6PDH and LDH) showed that NaN3 increased LDH while kolaviron reduced LDH in the brain tissue homogenate (P < 0.001). In addition kolaviron treatment before (P < 0.001) or after (P < 0.05) NaN3 treatment also reduced LDH expression; thus supporting its role in suppression of oxidative stress. Interestingly, NF deposition increased in the Pfc after kolaviron treatment while Kv/NaN3 showed no significant change in NF when compared with the control. In furtherance, NaN3 and NaN3/Kv caused a decrease in NF deposition (degeneration). Ultimately, the protective effect of KV administered prior to NaN3 treatment was confirmed through p53 expression; which was similar to the control. However, NaN3 and NaN3/Kv caused an increase in p53 expression in the Pfc neurons (cell cycle dysregulation). We conclude that kolaviron is not neurotoxic when used at 200 mg/Kg BW. Furthermore, 200 mg/Kg of kolaviron administered prior to NaN3 treatment (Kv/NaN3) was neuroprotective when compared with Kolaviron administered after NaN3 treatment (NaN3/Kv). Some of the observed effects of kolaviron administered before NaN3 treatment includes reduction of astroglia activation, absence of astroglia scars, antioxidation (reduced NSE and LDH),...

The interaction between MDMA and Nicotine affects multiple brain centres and neurotransmitter systems (serotonin, dopamine and glutamate) involved in motor coordination and cognition. In this study, we have elucidated the effect of prolonged (10 days) MDMA, Nicotine and a combined Nicotine-MDMA treatment on motor-cognitive neural functions. In addition, we have shown the correlation between the observed behavioural change and neural structural changes induced by these treatments in BALB/c mice. We observed that MDMA (2 mg/Kg body weight; subcutaneous) induced a decline in motor function, while Nicotine (2 mg/Kg body weight; subcutaneous) improved motor function in male periadolescent mice. In combined treatment, Nicotine reduced the motor function decline observed in MDMA treatment, thus no significant change in motor function for the combined treatment versus the control. Nicotine or MDMA treatment reduced memory function and altered hippocampal structure. Similarly, a combined Nicotine-MDMA treatment reduced memory function when compared with the control. Ultimately, the metabolic and structural changes in these neural systems were seen to vary for the various forms of treatment. It is noteworthy to mention that a combined treatment increased the rate of lipid peroxidation in brain tissue.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, progressive paralysis and finally death. Despite the research efforts, currently there is no cure for ALS. In recent years, multiple epigenetic mechanisms have been associated with neurodegenerative diseases. A pathological role for histone hypoacetylation and the abnormal NF-κB/RelA activation involving deacetylation of lysines, with the exclusion of lysine 310, has been established in ALS. Recent findings indicate that the pathological acetylation state of NF-κB/RelA and histone 3 (H3) occurring in the SOD1(G93A) murine model of ALS can be corrected by the synergistic combination of low doses of the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator resveratrol and the histone deacetylase (HDAC) inhibitors MS-275 (entinostat) or valproate. The combination of the epigenetic drugs, by rescuing RelA and the H3 acetylation state, promotes a beneficial and sexually dimorphic effect on disease onset, survival and motor neurons degeneration. In this mini review, we discuss the potential of the epigenetic combination of resveratrol with HDAC inhibitors in the ALS treatment.