Current Pharmaceutical Design - Volume 24, Issue 17, 2018

Dementia has become a major health concern for the aging population of the United States. Studies indicate that participation in moderate exercise, with training, has been shown to have a beneficial impact on cognition. Thus, exercise and its effects on cognitive function has become an important area of research. This review summarizes the current literature on the potential mechanisms of the benefits of exercise for cognitive function.

Objective: Obsessive-compulsive Disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. This demonstrates the need for more targeted therapeutics. Recent preclinical and clinical studies have implicated the dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. Moreover, there are studies suggesting that neuroimmune abnormalities may play an important role in the pathogenesis of OCD. N-acetyl cysteine (NAC) is a safe and readily available agent that would modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. The modulation of inflammatory pathways may also play a role in the benefits seen following NAC treatment. Therefore NAC can be considered a neuroprotective agent. Methods: This paper explores the role of NAC in the treatment of OCD conditions refractory to first-line pharmacological interventions, reviewing the clinical studies published in the last decade. Results: The possible benefit mechanisms of NAC for this disorder will be discussed, as well as the role of vitamin D supplementation, given its specific property of stimulating the formation of glutathione in the brain. Conclusion: Nutraceutical supplementation in treatment resistance OCD may be important not only for improving obsessive-compulsive symptomatology, but also from a psychological perspective, given its better acceptance by the patients compared to pharmacological treatment.

GABAA receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including α1-6, β1-3, γ1-3, δ, ε, π,  and ρ1-3. The majority of receptors are comprised of α, β and γ or δ subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are α1βγ2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to αβγ, the binary αβ receptors lack a benzodiazepine α-γ2 interface. In pentameric αβ receptors, the third subunit is replaced with either an α1 or a β3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2α:3β or 3α:2β. The consequence of this is that 3α:2β receptors contain an α-α interface whereas 2α:3β receptors contain a β-β interface. Apart from the replacement of γ by α1 or β3 in binary receptors, the incorporation of ε subunit into GABAA receptors might be more complicated. As the ε subunit is not only capable of substituting the γ subunit, but also replacing the α/β subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs.

Background: The present study aimed to assess the efficacy of omega-3 in treating ROP in premature infants. Methods: This randomized double-blinded controlled trial was performed on 160 premature infants with gestational age lower than 32 weeks and birth weight < 1500 grams who were at risk of ROP development (Tehran, Iran-2013). Children were randomly assigned to two groups. The intervention group received 300 mg omega-3 daily and the control group received sterile water as the placebo. The severity of ROP was defined according to the International Classification of ROP. Results: The frequency of ROP was 7.5% in the group received omega-3 and 20.0% in the placebo group with a significant difference (p = 0.021). Regarding the severity of ROP in the intervention group, ROP grade I was found in two patients and ROP grade II in four patients; while ROP grade I, II, and III were revealed in 6, 6, and 4 patients in placebo group indicating a significant difference between the two groups (p = 0.001). Using the multivariate logistic regression modeling with the presence of gender, gestational age, and birth weight, the use of omega-3 was associated with reduced risk for ROP (p = 0.045). Conclusion: The use of omega-3 supplement can be an appropriate treatment option for the treatment of ROP in premature infants.

Background: The research on the improvement of epilepsy therapy is constantly growing. Valproyl-LPhenylalanine (VPA-Phen) and N-valproyl-L-tryptophan (VPA-Tryp) were synthesized to increase the antiepileptic efficacy of valproic acid. Methods: VPA-Phen and VPA-Tryp were comparatively tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 mM) of VPA-Phen or VPA-Tryp. Both burst duration and interburst frequency, during and after treatment, were off-line compared with baseline values. For both parameters, either the latency or the duration of drug-induced statistically significant responses was calculated, as well as the response magnitude. Results: VPA-Phen significantly reduced both burst frequency and duration. Comparative analyses show that VPA-Phen and VPA-Tryp exert almost equivalent actions on both latency and magnitude of the observed inhibitory effects. The main observed difference between the two tested molecules concerned the duration of inhibitory effects, since VPA-Phen-dependent actions on both burst rate and duration were significantly shorter than the VPA-Tryp-induced ones. In addition, in some slices the above reported inhibitory responses were preceded by a “paradoxical” transient increase, more present at lower drug concentrations. Conclusions: Both VPA-Phen and VPA-Tryp exert significant inhibitory effects on hippocampal burst activity parameters. Although of comparable magnitude, VPA-Phen-dependent effects have a shorter duration than VPATryp- induced ones. Nevertheless, the present results confirm that the conjugation between VPA and aminoacids represents a valid tool to improve the efficacy of antiepileptic drugs and, as well as for VPA-Tryp, propose VPAPhen as a novel VPA derivative with enhanced pharmacological features.

The time window for neuroprotection during ischemic brain stroke is short, and hence, development of neuroprotectants is critical to extend this time window. This study sought to verify if muco-adhesive chitosan coating improves the neuroprotective potential of the pre-proven C-Phycocyanin-pertaining liposome (C-Pc liposome). The use of chitosan-coated liposomes extended the neuroprotective time window by 6 h after occlusion, and further improved the neuroprotection efficiency of the C-Pc liposome in a rat Middle Cerebral Artery Occlusion (MCAO) model. Beneficial changes in mRNA expressions of antioxidants, inflammatory cytokines and glia scar proteoglycans were evident in the C-Pc liposomes. In addition, in the cultured astrocytes, the chitosan- coated C-Pc liposome expressed anti-oxidative activity without cytotoxicity.

Background: Fatty acids are common dietary nutrients particularly in economically developed countries. Research has revealed that omega-3fatty acids exert beneficial effects in the progression of atherosclerosis and cardiovascular disease. Moreover, eicosapentaenoic acid and docosahexaenoic acid possess a number of biological actions which improve cardio-metabolic health. Omega-3 fatty acids display remarkable anti-oxidant, anti-inflammatory, anti-thrombotic and anti-arrhythmogenic actions. Furthermore, they improve the levels of triglycerides, glucose metabolism and endothelial function. Methods: The aim of this review article is to present physical, biochemical and biological properties of omega-3 fatty acids and summarize the most important mechanisms of action on arterial wall properties and arterial stiffness in atherosclerosis. Results: Omega-3 fatty acids may prevent the progression of atherosclerosis. Endothelial dysfunction and arterial stiffness can be regulated by the supplementation of omega-3 fatty acids. Conclusion: The mechanisms of action of omega-3 fatty acids on cardiovascular health and arterial stiffening have been established. However, further research is needed in order to translate the conflicting results among the studies and improve the therapeutic options of cardiovascular disease.

Purpose: The purpose of this study was to determine the relationship between Kinesin like protein 6 (KIF6) gene Trp719Arg and major cardiovascular events (MACEs) risk in subjects who received statin therapy. Methods: PubMed, EmBase, and the Cochrane Library were searched from inception through September 2017. The selected studies evaluated the association of Trp719Arg with MACEs in individuals who received statins. Relative risk (RR) and 95% confidence interval (CI) were used to evaluate the effect of statin therapy on MACEs in subjects carrying polymorphisms, and the odds ratio (OR) and 95% CI were used to evaluate the relationship between Trp719Arg and MACE risk in individuals who received statins, using the random-effects model. Results: Seven studies were included (N=48,885). Overall, we found that statin therapy significantly reduced the risk for MACEs in subjects carrying ArgArg (RR: 0.79; 95% CI: 0.69-0.90; P=0.001), ArgTrp (RR: 0.71; 95% CI: 0.60 -0.83; P<0.001), ArgArg+ArgTrp (RR: 0.71; 95% CI: 0.63 -0.81; P<0.001), and TrpTrp (RR: 0.79; 95% CI: 0.73-0.85; P<0.001). Furthermore, there was no significant difference between subjects carrying ArgArg and those carrying TrpTrp (OR: 1.11; 95% CI: 0.92-1.34; P=0.265). However, ArgTrp (OR: 1.29; 95% CI: 1.07-1.55; P=0.007) and ArgArg+ArgTrp (OR: 1.26; 95% CI: 1.05-1.51; P=0.012) were associated with an increased risk for MACEs when compared with TrpTrp. Conclusions: Statin therapy significantly reduced the risk for MACEs in subjects carrier specific KIF6 gene Trp719Arg polymorphisms. Further, subjects carrying ArgTrp or ArgArg+ArgTrp had a greater incidence of MACEs as compared with TrpTrp when they received statins.

Background: The treatment of type 2 diabetes mellitus (T2DM) is complex; only a few patients successfully attain glycemic targets with monotherapy, most requiring drug combination therapy. Methods: The goal of this review was to identify in PubMed the complimentary ways of action leading to clinical benefit (in lowering HbA1c, body weight, renal, and cardiac risk factors and events) of the combination of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA). Results: SGLT2i, an emerging class of antidiabetic agents with an insulin-independent mechanism of action, are suitable for use in combination with any other class of antidiabetics, including insulin. The use of SGLT2i causes a reduction in Cardiovascular Disease (CVD) morbidity (mainly heart failure-HF) as well as total and CVD mortality. Besides insulin, SGLT2i may also be combined with incretin-based therapies, such as GLP-1 RA. The latter appears to reduce the rate or the progression of both macrovascular (mainly myocardial infarction-MI and stroke) and microvascular complications of DM, having a beneficial effect on all-cause mortality and CVD mortality, as well as CVD events. SGLT2i and GLP-1 RA may have a synergic effect on glucose reduction, weight reduction, renal impairment (both an independent lethal disease and a CVD risk factor) improvement, and cardiac event reduction, because the first reduces HF and related events and the second decreases CVD risk (mainly MI and stroke). Both also reduce total mortality, especially when combined with a statin. Conclusion: The combination of metformin with SGLT2i, GLP-1 RA, and a potent statin, in high CVD risk patients with DM, is expected to substantially reduce CVD mortality and morbidity, improving the quality of life of patients with DM at the same time. Prospective studies are needed to confirm this finding.

Cardiovascular Disease (CVD) is one of the most important causes of morbidity and mortality, and associated with an important economic burden globally. Over the last decade, the prevalence of CVD has been rising globally, and is now associated with millions of death annually in both developed and developing countries. There is good evidence that the immune system is involved in the pathophysiology of CVD. Toll-like receptors (TLRs) and their down-stream signaling pathways play an important role in the immune system. Recent studies have suggested that the TLRs are involved in atherogenesis, including stroke, myocardial infarction, ischemiareperfusion injury, cardiac remodeling and development of Heart Failure (HF). In this review we have summarized the recent studies investigating the role of TLRs in CVD and the potential for using TLRs signaling pathways as a therapeutic target in CVD.

Background: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. Methods: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 μM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

Background: Telomerase Activator 65 (TA-65), a compound extracted from Astragalus membranaceus has been used in Chinese traditional medicine for extending lifespan. Scarce information exists on the effects of TA-65 on parameters of metabolic syndrome (MetS). Methods: We recruited 40 patients with MetS to determine the effects of TA-65 on dyslipidemias, hypertension, and oxidative stress in this at-risk population. The study was a double-blind, randomized crossover design in which patients were allocated to consume either 16 mg daily of a TA-65 supplement or a placebo for 12 weeks. Following a 3-week washout, participants were allocated to the alternate treatment for an additional 12 weeks. Anthropometric and biological markers were measured at the end of each treatment. Plasma lipids, glucose, CReactive Protein (CRP), liver enzymes, and glycosylated hemoglobin were measured using a Cobas c-111. Inflammatory cytokines were measured by Luminex technology and markers of oxidative stress by the use of spectroscopy. Results: Compared to the placebo period, HDL cholesterol (HDL-C) was higher while body mass index, waist circumference, and the LDL/HDL ratio were lower (p < 0.05) during TA-65 treatment. In addition, plasma tumor necrosis factor-α (TNF-α) was lower during the TA-65 period (p< 0.05). Positive correlations were observed in changes between the placebo and the TA-65 periods in HDL-C and CRP (r = -0.511, p < 0.01), alanine aminotransferase (r = -0.61, p < 0.001) and TNF-α (r = -0.550, p < 0.001) suggesting that the favorable changes observed in HDL were associated with decreases in inflammation. Conclusion: TA-65 improved key markers of cardiovascular disease risk, which were also associated with reductions in inflammation.