CNS & Neurological Disorders - Drug Targets - Volume 11, Issue 2, 2012

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Epilepsy is a devastating neurological disorder in which those afflicted can gain benefit from specific treatments based on their genetics and geographic location. Currently the prevalence of epilepsy is estimated at 0.5-3% of the world-wide population, and is increasing in developing countries. In order to make more accurate assessments of the prevalence of epilepsy, we applied the capture-recapture method in a 12-month study of epilepsy in a population from the Sharur district of Nakhichevan Autonomous Republic, Azerbaijan with 114,451 people from sixty nine villages and towns. The following methods were applied to determine epilepsy: Door To Door (DTD) survey, Non-Medical Source (NMS), and Medical Source. Using these three techniques, 1,032 patients with epilepsy (9.02/1000) were included in our study. The DTD survey determined 627 patients with epilepsy (5.48/1000) and 247 (2.16/1000) from the NMS methods versus 158 (1.38/1000) from the Medical Source (MS) methods. Applying the capture-recapture method, NMS, and DTD methods, the number of epilepsy cases increased to 1,330 (11.62/1000) [95% CI: 10.21-13.03]. The combinations of these methods show that 887 people (7.75/1000) have a diagnosis of epilepsy. Multiple epidemiological tasks used in our study can be used to estimate clinical signs and/or markers in future applications for the determination and development of treatment strategies for this devastating disease in the third world countries such as the Nakhichevan Autonomous Republic of Azerbaijan.

Belief and expectation are part of placebo effect. Migraine patients are characterized by a dysfunctional modulation of pain processing, though a clear placebo effect emerges in clinical trials. The aim of the study was to evaluate the effect of visual and verbal suggestion on subjective pain sensation and cortical responses evoked by CO2 painful laser stimuli in migraine without aura patients vs healthy controls. Twenty-six patients were recorded during the inter-ictal phase and compared to 26 sex and age-matched controls. The right hand and the right supraorbital zone were stimulated during a not conditioned and a conditioned task, where laser stimuli were delivered after a verbal and visual cues of decreased (D), increased (I) or basal (B) intensity, which was left unmodified during the entire task. In control subjects pain rating changed, according to the announced intensity, while in migraine patients the basal hyper-algesia remained unmodified. The N1 and N2 amplitudes tended to change coherently with the stimulus cue in controls, while an opposite paradoxical increase in decreasing condition emerged in migraine. The P2 amplitude modulation was also reduced in migraine, differently from controls. The altered pattern of pain rating and N2 amplitude modulation concurred with frequency of migraine, disability and allodynia. In controls suggestion influenced cortical pain processing and subjective pain rating, while in migraine a peculiar pattern of cortical activation contrasted external cues in order to maintain the basal hyper-algesia. This scarce influence of induced suggestion on pain experience seemed to characterize patients with more severe migraine and central sensitization.

Arachnoid cysts are congenital benign cysts accounting for approximately 1% of all intracranial mass lesions. Uncal herniation due to arachnoid cyst is a rare mode of presentation. It is hypothesized that only tension arachnoid cyst could cause the life-threatening condition that results from a progressive deterioration and worsening of a simple and usually congenital arachnoid cyst, associated with the formation of a “ball valve” at the point of an opening on the cyst wall. To-date only one case of an arachnoid cyst causing Uncal herniation has been reported to the best of our knowledge. We present a rare case of uncal herniation in a 60-year-old lady caused by a giant left temporal arachnoid cyst. She presented to us in emergency room after experiencing headaches since last one week followed by vomiting, seizures, and altered state of consciousness. She was operated immediately and marsupialization of the arachnoid cyst was performed. She showed good recovery. Although arachnoid cyst is a benign slowly growing pathology, it can lead to Uncal herniation as a ”tension“ arachnoid cyst, possible due to ”ball-valve“ mechanism. Elective treatment should be considered to prevent progressive significant enlargement of cyst.

Background and purpose: Excitotoxic central nervous system (CNS) response is believed to be important in the pathophysiology of irreversible sequelae of anoxia and brain trauma. Furthermore, the sodium pump has been associated with functional CNS syndromes such as migraine and epilepsy. Thus, a detailed description of the kinetics of excitotoxic responses elicited by glutamatergic pathway activation and sodium pump blockade can be useful in pre-clinical research. This should be aimed at minimizing the brain damage due to anoxia or trauma or the prophylaxis of functional syndromes. Experimental Approach: The kinetics of the intrinsic optical signals of excitotoxic responses were examined in detail following N-methyl-D-aspartic acid or ouabain extrinsic pulses in in vitro retinas and compared to optical profiles of retinal spreading depression waves in intact retinae in chicken eye-cups. Additional experiments recorded field potentials simultaneously with the intrinsic optical signals. The protective effects of extracellular magnesium and glutathione were also examined. Results: The initial phase (10 min) of the excitotoxic responses were very similar, however the final outcome was different: usually, irreversible damage was restricted to patches of tissue following N-methyl-D-aspartic acid pulses. By contrast, extrinsic ouabain experiments resulted in whole tissue death even with concentrations as low as 10 nM, except in three experiments in which glutathione at physiological concentrations was added to the perfusion 60 min before the pulse. Conclusion: the glial sodium pump must be a receptor of endogenous cardiac glycosides and its blockade can trigger excitotoxicity with a non-synaptic mechanism. The demonstration of glutathione protective effect suggests the importance of the transducer role of this membrane ATPase in the CNS.

This study describes molecular interactions between human brain acetylcholinesterase (AChE) and the well known anti-neoplastic drug, methotrexate (MTX) and its comparison to ‘AChE-cyclophosphamide (CP) interactions’ that we reported previously. Docking between MTX and AChE was performed using ‘Autodock4.2’. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of MTX within the ‘acyl pocket’ as well as ‘catalytic site’ of AChE to permit docking. However, docking of CP to AChE is largely dominated by hydrophobic interactions. Such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of MTX. Scope still remains in the determination of the three-dimensional structure of AChE-MTX complex by X-ray crystallography to validate the described data. The current computational study supports our previous experimental study which concluded a mixed inhibition model for AChE-inhibition by MTX. Furthermore, the present report confirms that MTX is a more efficient inhibitor of human brain AChE compared to CP with reference to Ki and ΔG values.

This study analyzed the effect of intra-ventrolateral periaqueductal grey (VL PAG) cannabinoid receptor (CB) stimulation on pain responses and rostral ventromedial medulla (RVM) neural activity in the chronic constriction injury (CCI) model of neuropathic pain in rats. Interaction between CB1 and metabotropic glutamate 1 and 5 (mGlu1/mGlu5) receptors was also investigated together with the expression of the CB1 receptor associated G??i3 and cannabinoid receptor interacting 1a (CRIP 1a) proteins and the endocannabinoid synthesising and hydrolysing enzymes. In rats not subjected to CCI-induced pain, intra-VL PAG (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) (2-4-8 nmol), a CB receptor agonist, increased the tail flick latency and changed the ongoing activity of RVM OFF and the tail flick-related activity of the ON and OFF cells, accordingly. These effects were prevented by SR141716A and MPEP, selective CB1 and mGlu5 receptor antagonists, respectively, though not by CPCCOEt, a selective mGlu1 receptor antagonist. A higher dose up to 16 nmol of WIN 55,212-2 was necessary to increase tail flick latency and change ON and OFF cell activity in CCI rats. Consistently, CCI rats showed a decrease in the expression of CB1 receptors, NAPE-PLD, Gαi3 and CRIP 1a proteins;the expression of diacylglycerol lipase A (DAGLA) was increased while fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) did not change. As in control rats, MPEP and SR141716A also blocked WIN 55,212-2- induced effects in CCI rats. These data demonstrate a down regulation of the endocannabinoid system and a functional interaction between mGlu5 and CB1 receptors for cannabinoid-mediated effect in the PAG-RVM pain circuitry in neuropathic pain inflicted rats.

Hypericum perforatum is a medicinal herb possessing ability for protecting neurons from oxidative stress. Since nitric oxide (NO) may be protective against oxidative stress-induced cell death as occurs in glucose deprivation (GD)-induced neurotoxicity, whether a standardized extract of H. perforatum (HP) increases the NO-mediated neuroprotective effect in GD-PC12 cells was investigated. Induced death in PC12 cells by GD exposure for 18 h was partially prevented by cell incubation with sodium nitroprusside (SNP), a NO-donor. SNP increased survival and nitrite production in GD-cells in a concentration-dependent manner. Co-incubation of cells with 10 μM SNP plus 50-100 μg/ml HP under GD insult significantly prevented GD-induced cell death to a higher extent than SNP alone as shown by an augmentation of cell survival and intracellular bcl-2 levels and a decrease of lipid peroxidation, caspase-3 activation and PARP cleavage. Cytoprotection by the NO-donor was almost abolished by the use of a NO scavenger and potentiated by the presence of superoxide dismutase. SNP and/or HP neuroprotection on GD-cells was significantly reversed by rotenone treatment. These results suggest that: (1) SNP could protect PC12 cells from GD-induced cytotoxicity through NO generation and (2) the enhancement of the SNP-mediated neuroprotective effect on GD-cells by HP might arise in part through scavenging of reactive oxygen species (ROS) and inhibition of mitochondrial dysfunction associated with the hypoglycemic episode. This current finding might highlight the development of therapeutic strategies aimed at manipulating NO-donors in combination with herb supplements containing ROS scavenger compounds for prophylaxis from brain ischemia.

Parkinson’s disease (PD) is characterized as a neurodegenerative movement disorder presenting with rigidity, resting tremor, disturbances in balance and slowness in movement. An important pathologic feature of PD is the presence of Lewy bodies. The primary structural component of Lewy bodies are fibrils composed primarily of alpha-synuclein, a highly conserved 140 amino acid protein that is predominantly expressed in neurons and which may play a role in synaptic plasticity and neurotransmission. Numerous studies suggest the aggregation and modification of alpha-synuclein as a key step leading to Lewy body formation and neuronal cell loss associated with PD. Because of the central role of alpha-synuclein in PD, it represents a novel drug target for the possible treatment of this disease. In this review, an overview of the role of alpha-synuclein in PD will be discussed with an emphasis on recent studies utilizing an immunization approach against alpha-synuclein as a possible treatment option for this debilitating disease.

Insomnia is common among elderly people and nearly 30 to 40% of the adult population also suffer from insomnia. Pharmacological treatment of insomnia include the use of benzodiazepine and non-benzodiazepine drugs like zolpidem, zaleplon,Zopiclone. Although these drugs improve sleep ,their usage is also associated with number of adverse effects, Melatonin ,the hormone secreted by the pineal gland of all animals and human beings has been used for treatment of insomnias,since the timing of its secretion in humans as well as in most of the animals coincides with the increase of nocturnal sleep propensity.Because of its short half life,melatonin slow release preparations were introduced for treatment of insomnia. Recently ramelteon ,a selective MT1,MT2 receptor agonist with greater efficacy of action in treating insomnia has been used clinically and has been found effective in improving sleep quality ,sleep efficacy and also in reducing the sleep onset time when compared to melatonin or slow melatonin preparations.The mechanism of action of ramelteon in improving sleep is discussed in the paper. Another melatonergic drug agomelatine besides acting on MT1/MT2 receptors also displays 5-HT2c antagonism and this drug has been found effective as a novel antidepressant for treating major depressive disorders.Agomelatine besides causing remission of depressive symptoms also improves sleep quality and efficiency. Other antidepressants depressants that are in clinical use today do not improve sleep. There are other melatonergic drugs like tasimelteon ,6-chloromelatonin.But ramelteon and agomelatine deserve special attention for treatment of insomnia and sleep disturbances associated with depressive disorders and have promising role for treatment of sleep disorders.