Current Pharmaceutical Design - Volume 21, Issue 34, 2015

Control of GABA neurotransmission at the pre-synaptic site occurs substantially through the activation of the glutamic acid decarboxylase (GAD) enzymes GAD65 and GAD67. Concentrations of GAD65 and GAD67 are controlled either by transcription or by mRNA splicing and importantly the activities of these key enzymes are regulated by post-translational mechanisms. Important post-translational modifications include proteolytic cleavage, phosphorylation and palmitoylation. A truncated form of GAD65 (tGAD65) is more active than full length GAD65 (fGAD65) whereas, by contrast, truncated GAD67 (tGAD67) is less active than full length GAD67 (fGAD67). The protein responsible for cleaving of fGAD65 and fGAD67 is mu-calpain. GABA neurotransmission is dependent upon whether GAD is associated with synaptic vesicles (SV) and calpain performs a vital role by generating the highly active tGAD65 resulting in augmented GABA synthesis and wrapping uptake into SV. Studies on GAD phosphorylation demonstrate that GAD65 is regulated through phosphorylation by PKC while GAD67 is inhibited through phosphorylation by PKA. Cysteine residues 455 and 446 in GAD67 and GAD65 individually are critical for full GAD regulation. Interaction with the cofactor pyridoxal 50-phosphate (PLP) at this these respective locations regulate the switch between PLP-bound active holoGAD and an unbound active apoGAD form. Transient switching to the PLP bound active holoGAD is integral to GABA neurotransmission. Specific to GAD65 but not GAD67 is palmitoylation by HIP14 which facilitates GAD65 anchoring to SV and enhances the contribution of vesicular GABA to neurotransmission. From studies on a rodent stroke model calpain-mediated cleavage of GAD enzyme has been shown to occur under pathological conditions resulting in less SV refilling and depletion of existing pools of SV releasable GABA.

Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit, but unfortunately, it has been only successful in terms of developing symptomatic treatments. Aβ deposition and neurofibrillary tangles along with neuron and synapse loss are associated with neurotransmitter dysfunction and have been recognized as hallmarks of AD. Furthermore, clinical and preclinical studies point to this neurotransmitter dysfunction as a main factor underlying both cognitive and neuropsychiatric symptoms of the illness. Cholinergic deficit in AD prompted the use of cholinesterase inhibitors as the symptomatic treatment of cognitive decline in AD, however this therapeutic approach provides only modest benefit in the majority of patients. Hence, nowadays research is focused on investigating compounds that could restore cognition and memory in AD patients. GABA is the primary inhibitory neurotransmitter in the central nervous system and GABAergic neurons provide extensive innervation to cholinergic and glutamatergic neurons. It has been shown that dysfunction of the GABAergic system may contribute to cognitive impairment in humans. Significant reductions in GABA levels have been described in severe cases of AD, which could be underlying the behavioral and psychological symptoms of AD. This review examines the involvement of the GABAergic system in both cognitive and non-cognitive behavioural symptoms in AD, providing some pointers for rational drug development.

Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical, psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results did not show significant efficacy and the trials were terminated. The advances in the understanding of the GABA system in FXS have shifted the focus of treatment trials to GABA agonists, and a new wave of promising clinical trials is under way. Ganaxolone and allopregnanolone (GABA agonists) have been studied in individuals with FXSD and are currently in phase II trials. Both allopregnanolone and ganaxolone may be efficacious in treatment of FXS and FXTAS, respectively. Allopregnanolone, ganaxolone, riluzole, gaboxadol, tiagabine, and vigabatrin are potential GABAergic treatments. The lessons learned from the initial trials have not only shifted the targeted system, but also have refined the design of clinical trials. The results of these new trials will likely impact further clinical trials for FXS and other genetic disorders associated with ASD.

Central nervous system is not spared from the deleterious effects of diabetes, since several studies have described neuropsychological and neurobehavioral changes in diabetic subjects, suggesting that diabetic encephalopathy should be recognized as a complication of this complex metabolic disorder. In fact, psychiatric manifestations may accompany this encephalopathy, since the prevalence of depression in diabetic patients is much higher than in the general population. Furthermore, evidences from preclinical and clinical studies suggest that GABA plays a role both in the pathophysiology of the diabetic encephalopathy-related depression. So, this review addresses the GABAergic modulation in diabetic encephalopathy-related depression. Data presented from literature support the association between GABA and depressive- like behaviors in diabetic encephalopathy, being this neurotransmitter a potential target for the treatment of diabetes, depression and related comorbidities.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and diseases that associate a deficiency in GABA might benefit from GABAergic drugs. Cerebellar Purkinje cells employ GABA as a neurotransmitter. Cortical cerebellar atrophy (CCA) shows Purkinje cell loss, and ataxia caused by it was alleviated by gabapentin and pregabalin. Thus, CCA is proposed as a model of selective deficiency in GABA in the cerebellum, which benefits clinically from administration of GABAergic drugs, in a manner similar in which levodopa improves motor manifestations in Parkinson’s disease. Other ataxias also benefited clinically from GABAergic drugs, as adult-onset GM2 gangliosidosis, olivopontocerebellar atrophy, cerebellar ataxia with hypogonadism, spinocerebellar ataxias 1, 2 and 6, and adult-onset ataxia-telangiectasia. Complex neurochemical diseases, as multiple-system atrophy, had ataxia worsened by GABAergic drugs. Various disorders with a deficiency in GABA content had their manifestations relieved by admistration of GABAergic drugs, as one patient with progressive encephalomyelitis with rigidity, whose muscular spasms were suppressed by a combination of gabapentin and tiagabine, and another with diaphragmatic myoclonus, who required gabapentin and tiagabine for symptomatic control. On the contrary, GABAergic drugs were not effective in cervical dystonia, amyotrophic lateral sclerosis, Parkinson’s disease and progressive supranuclear palsy, presumably because a deficiency in GABA is not an essential neurochemical abnormality in these diseases. Research aimed at identifying effective therapies to treat cerebellar ataxias and other motor disorders of the central nervous system is warranted. Meanwhile, therapeutic tests with GABAergic drugs might yield clinical improvement in these diseases.

Since the first report about the presence of γ-aminobutyric acid (GABA) within the gastrointestinal (GI) tract, accumulating evidence strongly supports the widespread representation of the GABAergic system in the enteric milieu, underlining its potential multifunctional role in the regulation of GI functions in health and disease. GABA and GABA receptors are widely distributed throughout the GI tract, constituting a complex network likely regulating the diverse GI behaviour patterns, cooperating with other major neurotransmitters and mediators for maintaining GI homeostasis in physiologic and pathologic conditions. GABA is involved in the circuitry of the enteric nervous system, controlling GI secretion and motility, as well as in the GI endocrine system, possibly acting as a autocrine/paracrine or hormonal agent. Furthermore, a series of investigations addresses the GABAergic system as a potential powerful modulator of GI visceral pain processing, enteric immune system and carcinogenesis. Although overall such actions may imply the consideration of the GABAergic system as a novel therapeutic target in different GI pathologic states, including GI motor and secretory diseases and different enteric inflammatory- and pain-related pathologies, current clinical applications of GABAergic drugs are scarce. Thus, in an attempt to propel novel scientific efforts addressing the detailed characterization of the GABAergic signaling in the GI tract, and consequently the development of novel strategies for the treatment of different GI disorders, we reviewed and discussed the current evidence about GABA actions in the enteric environment, with a particular focus on their possible therapeutic implications.

Genome-wide studies have identified thousands of noncoding RNAs (ncRNAs) with no protein coding capacity. Among them, the long non-coding RNAs (lncRNAs), which are more than 200 nucleotides in length, recently are widely concerned for their crucial role in regulating biological processes and diseases. However, most lncRNAs are expressed at a very low level, and generally exhibit poor primary sequence conservation over evolution. Long non-coding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as NEAT2 (nuclear-enriched abundant transcript 2), is outstanding among the lncRNA family due to its evolutionarily high conservation and abundant expression throughout diferent mammalian species. Meanwhile, MALAT1 was one of the first lncRNAs that was demonstrated to be associated with a disease, namely non-small cell lung cancer (NSCLC). Subsequently, MALAT1 was identified in multiple types of physiological processes, such as alternative splicing, nuclear organization, epigenetic modulating of gene expression, and so on. Moreover, a growing number of evidences indicated that MALAT1 was also closely related to various pathological processes, ranging from diabetes complications to cancers.In this review, we will make a summary on current understanding of MALAT1 in different physiological or pathophysiological processes and discuss the potential therapeutic applications based on MALAT1 detection and inhibition.

Bone cancer pain (BCP) is still an intractable problem currently because the analgesic pharmacological intervention remains insufficient. Thus, the development of novel therapeutic target is critical for the treatment of BCP. Emerging evidence demonstrated that some chemokines and their receptors contribute to the induction and maintenance of BCP. In this article, we reviewed the current evidence for the role of different chemokines and their receptors (e.g. CXCL12/CXCR4, CXCL1/CXCR2, CCL2/CCR2, CCL5/CCR5, CX3CL1/CX3CR1 and CXCL10/CXCR3) in mediating BCP. By extensively understanding the involvement of chemokines and their receptors in BCP, novel therapeutic targets may be revealed for the treatment of BCP.

Coffee is among the most widespread and healthiest beverages in the world. It is known to be a highly rich source of biologically active natural metabolites which possess therapeutic effects (i.e. caffeine) and functional properties (i.e. chlorogenic acids). Therefore, coffee can be considered a drink which has different positive effects on human health such as cardioprotective, neuroprotective, hepatoprotective, nephroprotective, etc. However, heavy coffee consumption may be related to some unpleasant symptoms, mainly anxiety, headache, increased blood pressure, nausea, and restlessness. During the past two decades, several studies have indicated that there is a close correlation between consumption of coffee and incidence of depression. In addition, phytochemical studies showed that caffeine is the main responsible constituent for antidepressant effects of coffee through multiple molecular mechanisms. The aim of the present paper was to collect the latest literature data (from 1984 to 2014) on the positive and negative impacts of coffee consumption on the major depressive disorders and to clarify the role of bioactive constituents of coffee in the related different clinical trials. To the best of our knowledge, this the first review on this topic.

Background: Clopidogrel’s ability to inhibit platelet function determined its clinical usefulness. The role of CYP2C19*2 genotype on antiplatelet treatment is recently under question. Arterial wall properties and inflammation are key players in atherosclerosis development. Hence, we evaluated the impact of CYP2C19*2 genetic polymorphism on endothelial function, arterial stiffness and inflammation in coronary artery disease (CAD) patients receiving clopidogrel treatment. Methods and Results: In this study we enrolled 408 consecutive patients with stable CAD under dual antiplatelet therapy (clopidogrel 75mg/day, aspirin 100mg/day), 30 days after percutaneous coronary intervention. Measurement of flow-mediated dilation (FMD) of the brachial artery was used to evaluate endothelial function. Carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) was measured to estimate arterial stiffness. Real time polymerase chain reaction was used for the genotyping of CYP2C19*2. Levels of tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) were measured with ELISA. We found no difference in basic clinical and demographic characteristics nor in FMD, PWV, AIx and inflammatory status (p=NS for all) between CYP2C19 homozygotes for the wild type; carriers of reduced function allele and homozygotes for the reduced function allele. Conclusion: CYP2C19*2 loss of action polymorphism causes no impact on vascular function and inflammatory status in stable CAD patients receiving clopidogrel treatment.