CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 18, Issue 7, 2019

In today’s world, migraine is one of the most frequent disorders with an estimated world prevalence of 14.7% characterized by attacks of a severe headache making people enfeebled and imposing a big socioeconomic burden. The pathophysiology of a migraine is not completely understood however there are pieces of evidence that epigenetics performs a primary role in the pathophysiology of migraine. Here, in this review, we highlight current evidence for an epigenetic link with migraine in particular DNA methylation of numerous genes involved in migraine pathogenesis. Outcomes of various studies have explained the function of DNA methylation of a several migraine related genes such as RAMP1, CALCA, NOS1, ESR1, MTHFR and NR4A3 in migraine pathogenesis. Mentioned data suggested there exist a strong association of DNA methylation of migraine-related genes in migraine. Although we now have a general understanding of the role of epigenetic modifications of a numerous migraine associated genes in migraine pathogenesis, there are many areas of active research are of key relevance to medicine. Future studies into the complexities of epigenetic modifications will bring a new understanding of the mechanisms of migraine processes and open novel approaches towards therapeutic intervention.

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

Recent trial studies have shown that omega-3 supplementation can beneficially improve scores on the Expanded Disability Status Scale (EDSS), which is considered a gold standard for measuring disability and disease severity in Multiple Sclerosis (MS) patients, as well as reducing neuroinflammation. The present systematic review and meta-analysis aimed to evaluate the effect of omega-3 supplementation on EDSS and cytokines in MS. A systematic search was performed on Pubmed, Scopus and Cochrane Library up to October 2018. Studies were reviewed based on the Cochrane handbook, and the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Weighted Mean Difference (WMD) with 95% Confidence Intervals (CI) were pooled using a random effects model in order to compare the effects of omega-3 with placebos. Among 4 trials, omega-3 supplementation had no significant effect on EDSS scale (WMD: -0.07; 95% CI: -0.27 to 0.13; P=0.50), as well as serum levels of IL-1β (WMD: -7.67; 95% CI: -23.31 to 7.97; P=0.34) and IL-6 (WMD: -153.57; 95% CI: -455.36 to 148.23; P=0.32). However, omega-3 significantly reduced TNF-α concentration (WMD: -16.76; 95% CI: -18.63 to -14.88; P < 0.00001) compared to placebo. Overall, omega-3 supplementation may not have a clinically considerable impact on EDSS or proinflammatory markers. However, the existing trials are limited in this context, and further clinical trials are required to confirm the potential effects of the omega-3 supplement on MS disease management.

Background: Delirium is a disorder in awareness, attention and cognition. Pathophysiologically it is a response to stress. Postoperative delirium (POD) is a usual complication in aged patients following hip fracture surgery. Neuroinflammation is an important factor linked with the progress of POD. Though there are no efficient cures for delirium the endocannabinoid system may have a role in neuropsychiatric disorders. Objective: Therefore, we examined the effects of co-ultramicronized PEALut (co-ultraPEALut) in the LPS murine model of delirium and in elderly hip fractured patients. Methods: In the preclinical study, mice were injected intraperitoneally (i.p.) with Escherichia coli LPS (10 mg/kg). Co-ultraPEALut (1 mg/kg o.s.) was administered 1h before LPS injection or 1h and 6h after LPS injection or 1h before LPS injection and 1h and 6h after LPS. In the clinical study, the effects of Glialia® (co-ultramicronized 700 mg PEA + 70 mg luteolin) administration was evaluated in elderly hip fractured patients with an interventional, randomized, single-blind, monocentric study. Results: Administration of co-ultraPEALut to LPS-challenged mice ameliorated cognitive dysfunctions and locomotor activity; moreover, it reduced inflammation and apoptosis, while stimulating antioxidant response and limiting the loss of neurotrophins. In the clinical study, the results obtained demonstrated that administration of Glialia® to these surgical patients prevented the onset of POD and attenuated symptom intensity and their duration. Conclusion: Therefore, the results obtained enhanced the idea that co-ultraPEALut may be a potential treatment to control cognitive impairment and the inflammatory and oxidative processes associated with delirium.

Background: Alteration in electrophysiology, leading to cardiac dysfunction and subsequently a nontraumatic death is a complication of epilepsy known as “SUDEP” (Sudden Unexpected Death in Epilepsy). Aims: The present study was designed to understand the molecular changes and cardiac parameters during different phases of epileptogenesis in lithium-pilocarpine (Li-pilo) rat model of epilepsy. Methods: The animals were exposed to Li-pilo to induce Spontaneous Recurrent Seizures (SRS). Noninvasive blood pressure and electrocardiography was recorded at 7th, 28th and 75th day following pilocarpine administration, considered as latent, initial and late SRS phases, respectively. The serum biochemistry, cardiac histopathology, protein and mRNA expressions were studied, following electrocardiography on day 75. Results: The mean arterial pressure decreased during the latent phase, thereafter it progressively increased during the initial and the late SRS phases, as compared to the basal and the latent phase. Histopathological analysis of the heart sections indicated hypertrophy, degenerative changes and fibrous tissue deposition in epileptic animals, along with increased levels of lactate dehydrogenase and creatine kinase-MB in the serum. The expression of HIF-1α, phospho-S6, phospho-mTOR, TGF-β, collagen I and Na+/K+-ATPase α1 proteins, and mRNA levels of HIF-1α, mTOR, Rps6, Scn1b, Scn3b, Nav1.5 and TGF-β were increased in the cardiac tissue of epileptic animals, as compared to control. Conclusion: Our results conclusively showed that Li-pilo-induced SRS leads to cardiac dysfunction via mTOR pathway upregulation, thus suggested the regulatory control of mTOR pathway as a potential target for SUDEP management.

Background: Alzheimer’s disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer’s disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-β generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer’s disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer’s disease with Formononetin. Objective: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms. Methods: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg). Results: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1β and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-ΚB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice. Conclusion: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.