CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 14, Issue 4, 2015

This special number is dedicated to the Editorial Advisory Board Members of CNS & Neurological Disorders-Drug Targets.

NCS1 (neuronal calcium sensor-1) is a Ca2+-myristoyl switch protein of the NCS protein family involved in synaptic plasticity and neurotransmission via Ca2+-dependent regulation of dopamine D2 receptor and associated Gprotein coupled receptor kinase (GRK)-2. Overexpression of NCS1 in synaptic terminals results in accumulation of membrane-bound protein and its redundant regulatory activity associated with neurological disorders. Here, we have demonstrated that bovine photoreceptors contain NCS1 that is capable of a partially irreversible interaction with isolated photoreceptor membranes and implicated in Ca2+-dependent binding and regulation of GRK1 in vitro. Using NCS1- recoverin C-terminal chimeric construct (NR), it was found that the Ca2+-myristoyl switch of NCS1 is affected by its Cterminal segment downstream the fourth EF-loop of the protein, which is variable within the NCS family. NR retains structural stability and sensitivity to Ca2+, but interacts with photoreceptor membranes with lower affinity in a Ca2+- dependent fully reversible manner and displays altered GRK1 modulation. These data combined with fluorescent probing of surface hydrophobicity of NCS1, NR and recoverin suggest that the C-terminal segment of NCS1 regulates reuptake of myristoyl group under Ca2+-free conditions and participates in organization of the target-binding pocket of the protein. We point out a putative role of NCS1 in photoreceptors as a modulator of GRK activity and propose targeting of the Cterminal segment of NCS1 as an appropriate way for selective suppression of excessive membrane accumulation and aberrant activity of the protein in neurons associated with central nervous system dysfunctions.

We previously demonstrated that the intraperitoneal administration of palmitoylethanolamide (PEA) in mice with chronic constriction injury of the sciatic nerve evoked a relief of both thermal hyperalgesia and mechanical allodynia in neuropathic mice. Since diabetic neuropathy is one of the most common long-term complications of diabetes, we explored the ability of PEA to also relief this kind of chronic pain, employing the well established streptozotocin-induced animal model of type 1 diabetes. Our findings demonstrated that PEA relieves mechanical allodynia, counteracts nerve growth factor deficit, improves insulin level, preserves Langherans islet morphology reducing the development of insulitis in diabetic mice. These results suggest that PEA could be effective in type1 -diabetic patients not only as pain reliever but also in controlling the development of pathology.

Modafinil (MOD) it has to be considered as a wake-inducing drug to treat sleep disorders such as excessive sleepiness in narcolepsy, shift-work disorder, and obstructive/sleep apnea syndrome. Current evidence suggests that MOD induces waking involving the dopamine D1 receptor. However, little is known regarding the molecular elements linked in the wake-promoting actions of MOD. Since the D1 receptor activates the mitogen-activated protein kinase (MAP-K) cascade, it raises the interesting possibility that effects of MOD would depend upon the activation of MAP-K. Here we tested the expression of MAP-K in hypothalamus as well as pons after the microinjection of MOD (10 or 20μg/1μL) in rats into anterior hypothalamus, a wake-inducing brain area. Intrahypothalamic injections of MOD promoted MAP-K phosphorylation in hypothalamus and pons. Taken together, these results suggest that the wake-inducing compound MOD promotes the MAP-K phosphorylation.

Specific genetic anomalies or non-genetic factors could lead to epilepsy, but in various cases the underlying cause is unknown. Novel technologies, such as array comparative genomic hybridization, may reveal the copy number variants (CNVs), established as significant risk factor for epilepsy. This study carried out a high-density whole genome array- comparative genomic hybridization analysis with blood DNA samples from a cohort of twenty epilepsy patients to search for CNVs associated with epilepsy. Microdeletion of 14q31.1 was observed in four patients including two from the same family with loss of the NRXN3 gene; microdeletion of 15q12 in one patient with loss of the GABRG3 gene, and microduplication of 20q13.33 in three patients with loss of the gene group CHRNA4, KCNQ2, EEF1A2 and PPDPF were also found. These CNV findings were confirmed by real-time quantitative polymerase chain reaction. We have described, for the first time, numerous potential CNVs/genes implicated in epilepsy in the Saudi population. The study presents a better description of the genetic variations in epilepsy, and would eventually enable us to provide a foundation for understanding the critical genome regions which might be involved in the development of epilepsy.

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However, only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural plasticity of dendritic spines in otherwise naïve animals, particularly in brain regions mediating executive function. In the present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex (mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5- yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol- 2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats. Following once daily treatment for 10 consecutive days, coronal brain sections containing the mPFC underwent diolistic labeling and 3D image analysis of dendritic spines. Compared to vehicle treated animals, rats administered fenobam exhibited significant increases in dendritic spine density and the overall frequency of spines with small (<0.2 μm) head diameters, decreases in frequency of spines with medium (0.2-0.4 μm) head diameters, and had no changes in frequency of spines with large head diameters (>0.4 μm). Administration of CDPPB had no discernable effects on dendritic spine density or morphology, and neither CDPPB nor fenobam had any effect on spine length or volume. We conclude that mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity in otherwise naïve animals, and additional studies assessing their effects in combination with cognitive or behavioral tasks are needed.

Chronic stress has detrimental effects on brain structures and functions. Previous studies mainly focused on prefrontal cortex and hippocampus, given their well-described roles in cognition and emotive processing. Chronic stress also leads to changes in other neural circuits, such as the olfactory system. Olfactory deficits were reported in both animal models and patients with depression. The present review summarizes the evidence linking chronic stress to neuropathology in the olfactory system, and analyzes the potential mechanistic insights underlying these changes. We propose also that olfactory system-targeting therapies could be beneficial to certain symptoms of patients suffering from stress-related neurological diseases.

Aberrant expression of microRNAs (miRNAs) has been implicated in various neurological disorders (NDs) of the central nervous system such as Alzheimer disease, Parkinson’s disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia and autism. If dysregulated miRNAs are identified in patients suffering from NDs, this may serve as a biomarker for the earlier diagnosis and monitoring of disease progression. Identifying the role of miRNAs in normal cellular processes and understanding how dysregulated miRNA expression is responsible for their neurological effects is also critical in the development of new therapeutic strategies for NDs. miRNAs hold great promise from a therapeutic point of view especially if it can be proved that a single miRNA has the ability to influence several target genes, making it possible for the researchers to potentially modify a whole disease phenotype by modulating a single miRNA molecule. Hence, better understanding of the mechanisms by which miRNA play a role in the pathogenesis of NDs may provide novel targets to scientists and researchers for innovative therapies.

Vulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed.

Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-related diseases) have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, accumulating evidence supports a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.

Despite the medical and surgical advancements in the treatment of patients with acute infective endocarditis (IE), neurologic complications remain problematic. They can arise through various mechanisms consisting of stroke or transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, cerebral abscess, or encephalopathy. Most complications occur early during the course of IE and are characteristic to left-sided pathology of native or prosthetic valves. We present a case of a 46 year old male patient who presented to our clinic with mitral valve IE caused by coagulase negative staphylococcus. Although under correct antibiotic treatment, he continued to be feverish and started to present unspecific neurological symptoms (amnesia, confusion, asthenia and general malaise). The cerebral magnetic resonance imaging (MRI) revealed multiple cerebral abscesses. Because the patient was hemodynamically stable we decided to address the cerebral abscess first and the cardiac lesion second. The patient made a full recovery after undergoing antibiotic treatment and surgical procedures of drainage of the cerebral abscess and mitral valve replacement. After reviewing the literature regarding the management of patients with IE and cerebral complications and based on this particular case, we conclude that in select cases of stable patients with cerebral abscess and IE, the neurological lesion should always be addressed first and cardiac surgery should be performed second.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are widely distributed at different levels of the pain-processing pathway. Its action at the peripheral sensory nerve terminals has been found to be divergent; it can exert both pro- and anti-nociceptive effects, depending on the mode of administration (local or systemic) and the mechanism of the pain process (acute or chronic, inflammatory or neuropathic). In the central nervous system it exerts mainly neuronal excitation, leading to increased nociceptive signalling. Since the clinical data strongly suggest the involvement of PACAP in the pathophysiology of migraine, special emphasis is placed on examinations of its role and the mechanisms of activation of the trigeminovascular system. The intravenous administration of PACAP to migraineurs induces migraine-like headache and extracranial arterial dilatation. Furthermore, an increased PACAP concentration has been detected in the peripheral blood of patients during a migraine attack. Animal experiments have also revealed that PACAP elicits peripheral and central sensitization of the neuronal elements of the trigeminovascular system and evokes meningeal vasodilatation. This review summarizes data relating to the expression of PACAP and its receptors, and the main effects and mechanisms in the nociceptive pathways, with special emphasis on migraine. It is clear that PACAP plays an excitatory role in migraine, but its target and signalling pathways have not yet been elucidated due to the lack of non-peptide, selective agonists and antagonists. Identification of its up- and downstream regulations and receptorial molecular mechanisms might open up future perspectives for the development of novel analgesic drugs.

Cofilin-1 is a major actin depolymerizer in the central nervous system. It is a member of the ADF/cofilin family that regulates the dynamics of actin filaments. The activity of cofilin-1 is regulated by the modulation of phosphorylation at its Ser3 residue, and its proper function is crucial for the structure and proper function of neurons. Cofilin rods, pathological structures composed of cofilin and actin, form under stress conditions. A high cofilin/F-actin ratio, cofilin dephosphorylation and/or cofilin oxidation are three major mechanisms of cofilin rod formation. Cofilin rods can be divided into cytoplasmic rods and nuclear rods. Cytoplasmic rods have been proved to disrupt dendritic transportation, cause synaptic loss and impair synaptic function, which maybe associated with neurodegenerative diseases such as Alzheimer’s disease. On the other hand, the role of nuclear rods remains largely unknown. Further studies are needed to investigate the relationship and the underlying mechanisms of cofilin rod formation during the progression of various neurological diseases.