Current Pharmaceutical Design - Volume 25, Issue 33, 2019

Extracellular vesicles (EVs) are gaining tremendous importance in comprehending central nervous system (CNS) function and treating neurological disorders because of their role in intercellular communication and reparative processes, and suitability as drug delivery vehicles. Since EVs have lipid membranes, they cross the blood-brain barrier easily and communicate with target neurons and glia even deep inside the brain. EVs from various sources have been isolated, characterized, and tailored for promoting beneficial effects in conditions, such as brain injury and disease. Particularly, EVs isolated from mesenchymal stem cells and neural stem cells have shown promise for alleviating brain dysfunction after injury or disease. Such properties of stem cell-derived EVs have great importance for clinical applications, as EV therapy can avoid several concerns typically associated with cell therapy. This minireview confers the competence of EVs for improving brain function by modulating CNS injury and disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.

In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction and decline. Acetylcholinesterase (AChE) remains a highly feasible target for the symptomatic improvement of AD. Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AChE for myasthenia gravis had effectively proven that AChE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEIs) have been continued to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs which are under development and their respective mechanisms of actions.

Diabetes is an important metabolic disease affecting many organs and systems in the body. The nervous system is one of the body systems affected by diabetes and neuropathic complications are troublesome in diabetic patients with many consequences. As diabetes has deleterious influences almost on bodily systems, an integrative approach seems to be necessary accepting the body as a whole and integrating body systems with lifestyle and living environment. Like some traditional health systems such as Ayurveda, integrative approach includes additional modalities to overcome both diabetes and diabetic complications. In general, these modalities consist of nutraceuticals and plant products. Prebiotics and probiotics are two types of nutraceuticals having active ingredients, such as antioxidants, nutrient factors, microorganisms, etc. Many plants are indicated for the cure of diabetes. All of these may be employed in the prevention and in the non-pharmacological management of mildto- moderate diabetes. Severe diabetes should require appropriate drug selection. Being complementary, prebiotics, probiotics, plants and exercise may be additive for the drug therapy of diabetes. Similarly, there are complementary approaches to prevent and cure neurological and/or behavioral manifestations of diabetes, which may be included in therapy and prevention plans. A scheme is given for the prevention and therapy of comorbid depression, which is one of the most common behavioral complications of diabetes. Within this scheme, the main criterion for the selection of modalities is the severity of diseases, so that personalized management may be developed for diabetic patients using prebiotics and probiotics in their diets, plants and drugs avoiding possible interactions.

Background: The pathoetiology and pathophysiology of migraine are widely accepted as unknown. Methods: The current article reviews the wide array of data associated with the biological underpinnings of migraine and provides a framework that integrates previously disparate bodies of data. Results: The importance of alterations in stress- and pro-inflammatory cytokine- induced gut dysbiosis, especially butyrate production, are highlighted. This is linked to a decrease in the availability of melatonin, and a relative increase in the N-acetylserotonin/melatonin ratio, which has consequences for the heightened glutamatergic excitatory transmission in migraine. It is proposed that suboptimal mitochondria functioning and metabolic regulation drive alterations in astrocytes and satellite glial cells that underpin the vasoregulatory and nociceptive changes in migraine. Conclusion: This provides a framework not only for classical migraine associated factors, such as calcitonin-gene related peptide and serotonin, but also for wider factors in the developmental pathoetiology of migraine. A number of future research and treatment implications arise, including the clinical utilization of sodium butyrate and melatonin in the management of migraine.

Long noncoding RNAs (lncRNAs) constitute large portions of the mammalian transcriptome which appeared as a fundamental player, regulating various cellular mechanisms. LncRNAs do not encode proteins, have mRNA-like transcripts and frequently processed similar to the mRNAs. Many investigations have determined that lncRNAs interact with DNA, RNA molecules or proteins and play a significant regulatory function in several biological processes, such as genomic imprinting, epigenetic regulation, cell cycle regulation, apoptosis, and differentiation. LncRNAs can modulate gene expression on three levels: chromatin remodeling, transcription, and post-transcriptional processing. The majority of the identified lncRNAs seem to be transcribed by the RNA polymerase II. Recent evidence has illustrated that dysregulation of lncRNAs can lead to many human diseases, in particular, cancer. The aberrant expression of lncRNAs in malignancies contributes to the dysregulation of proliferation and differentiation process. Consequently, lncRNAs can be useful to the diagnosis, treatment, and prognosis, and have been characterized as potential cancer markers as well. In this review, we highlighted the role and molecular mechanisms of lncRNAs and their correlation with some of the cancers.

Background: For decades, a great deal of research work has been done to synthesize ellipticine and its derivatives because of their potential antitumor properties and anti-HIV activities. However, the resonance structures in different media, a low level of solubility at physiological pH and systemic toxicity have prevented the use of ellipticine as a therapeutic agent. Besides, the low yield and complex steps of ellipticine synthesis limit its application. Methods: A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated. Results: The synthesis process of ellipticine was optimized, and the total yield of the synthetic route was increased to 50% through several operation steps optimization. Fourteen ellipticine hexacyclic derivatives were synthesized. The synthetic compounds were screened for anti-tumor activity in vivo and in vitro, and some of the derivatives had good anti-tumor activity. Conclusion: Compared with ellipticine, the compound 1l showed higher antitumor activity and better tolerance to tumor models. The compound 1l treatment increased the percentage of late apoptotic cells from 3.1% (DMSO) to 21.6% (20.0 μM) in NCI-H460 cells. It also was observed the effect of 1l on G2 phase arrest was similar as that of ellipticine. The mechanism of action indicated compound 1l could be a topoisomerase IIα poison. These studies provided the basis for the pharmacodynamics and toxicology of ellipticine, and further clarifies the structureactivity relationship of antitumor activity of ellipticine.

Background: Pioglitazone is mainly used for the management of type 2 diabetes and other insulinassociated diseases. However, the molecular mechanism of pioglitazone can lead to an imbalance in bone metabolism, thus decreasing bone mass density (BMD) and increasing the risk for fractures. Objective: To demonstrate the effect of pioglitazone therapy on bone metabolism and fat mass. Methods: A comprehensive search of the PubMed, EMBASE, Web of Science and Cochrane Central databases for randomized controlled trials (RCTs) on the effect of pioglitazone therapy on BMD and fat mass was performed. The primary outcome measures were the measured values of BMD, percentage changes in BMD, measured values of bone turnover markers and bone metabolic hormones, changes in BMI, body and leg fat mass, and fracture rates. The final search was performed in May 2019. Results: Six RCTs were included. A total of 749 patients met the inclusion criteria. Pioglitazone therapy was shown to significantly reduce the BMD of the whole body, lumbar spine, and total hip and serum PTH levels and increase BMI, total body fat mass and leg fat mass. In addition, 30 mg/d and 30 mg/d initially for one month followed by 45 mg/d pioglitazone could reduce the BMD of the lumbar spine. Pioglitazone therapy exerted no significant influence on the BMD of the femoral neck, serum BSAP or 25-OHD levels, or fracture rates. Conclusion: Compared with placebo, pioglitazone therapy reduced BMD and serum PTH levels and increased fat mass and BMI with no difference in serum BSAP or 25-OHD levels or fracture rates; 30 mg/d pioglitazone was sufficient to reduce the BMD of the lumbar spine.