Anxiolytic effects of the melatonin MT2 receptor partial agonist UCM765: Comparison with melatonin and diazepam

Melatonin (MLT) is a neurohormone known to be involved in the regulation of anxiety. Most of the physiological actions of MLT in the brain are mediated by two high-affinity G-protein-coupled receptors, denoted MT₁ and MT₂. However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT₂-selective partial agonist, UCM765 to evaluate the involvement of MT₂ receptors in anxiety. Adult male rats were acutely injected with UCM765 (5–10–20 mg/kg), MLT (20 mg/kg) or diazepam (DZ, 1 mg/kg). Anxiety-related behaviors were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at the dose of 10 mg/kg showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. In the EPMT, animals treated with UCM765 (10 mg/kg) or MLT (20 mg/kg) spent more time in the open arms compared to vehicle-treated animals, but to a lesser extent compared to DZ (1 mg/kg). In the NSFT, all treatments similarly decreased the latency to eat in a novel environment compared to vehicle. UCM765 and MLT did not affect the total time and the number of entries into the central area of the OFT, but unlike DZ, did not impair locomotion. The anxiolytic effects of UCM765 and MLT in the EPMT and the NSFT were blocked using a pre-treatment with the MT₁/MT₂ antagonist luzindole (10 mg/kg) or the MT₂ antagonist 4P-PDOT (10 mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT₂-receptors may be considered a novel target for the development of anxiolytic drugs.     

Hearing impairment in Parkinson's disease: Expanding the nonmotor phenotype

The objective of this study was to evaluate hearing impairment in patients affected by Parkinson's disease compared with hearing scores observed in normal age‐ and sex‐matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinson's disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinson's Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory‐evoked potentials. Healthy age‐ and sex‐matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age‐dependent high‐frequency hearing loss in patients with Parkinson's disease compared with both normative values and values for healthy age‐ and sex‐matched controls (75/106 [71%], χ² = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], χ² = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory‐evoked potentials were normal in all patients. Our patients with Parkinson's disease showed age‐dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinson's disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because α‐synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise‐induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinson's disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis. © 2012 Movement Disorder Society     

Involvement of PACAP/ADNP Signaling in the Resistance to Cell Death in Malignant Peripheral Nerve Sheath Tumor (MPNST) Cells

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas able to grow under conditions of metabolic stress caused by insufficient nutrients or oxygen. Both pituitary adenylate cyclase-activating polypeptide (PACAP) and activity-dependent neuroprotective protein (ADNP) have glioprotective potential. However, whether PACAP/ADNP signaling is involved in the resistance to cell death in MPNST cells remains to be clarified. Here, we investigated the involvement of this signaling system in the survival response of MPNST cells against hydrogen peroxide (H₂O₂)-evoked death both in the presence of normal serum (NS) and in serum-starved (SS) cells. Results showed that ADNP levels increased time-dependently (6–48 h) in SS cells. Treatment with PACAP38 (10^?9 to 10^?5 M) dose-dependently increased ADNP levels in NS but not in SS cells. PAC₁/VPAC receptor antagonists completely suppressed PACAP-stimulated ADNP increase and partially reduced ADNP expression in SS cells. NS-cultured cells exposed to H₂O₂ showed significantly reduced cell viability (~50 %), increased p53 and caspase-3, and DNA fragmentation, without affecting ADNP expression. Serum starvation significantly reduced H₂O₂-induced detrimental effects in MPNST cells, which were not further ameliorated by PACAP38. Altogether, these finding provide evidence for the involvement of an endogenous PACAP-mediated ADNP signaling system that increases MPNST cell resistance to H₂O₂-induced death upon serum starvation.     

Prefrontal cortex controls human balance during overground ataxic gait

Purpose: 1) to verify if prefrontal cortex (PFC) is activated during over ground walking in ataxic patients, 2) to correlate the clinical parameters of gait with the PFC activation patterns. Methods: Fourteen patients and 20 healthy subjects were studied. Ataxia was assessed by the Scale for the Assessment and Rating of Ataxia (SARA). A 2-channel near-infrared system was used to investigate the changes in oxygenated ([O2Hb]t) and deoxygenated ([HHb]t) hemoglobin concentrations on the PFC during gait. [O2Hb] baseline-corrected activation values ([O2Hb]c) were calculated by the difference between [O2Hb]t and [O2Hb] during upright posture ([O2Hb]b). Results: [O2Hb]t was increased for both channels (respectively p < 0.01 and p = 0.01) only in the patients. No variation was observed in [HHB]t. The correlation coefficient between [O2Hb]c and the SARA gait score was respectively r: 0.878 (p < 0.01) and r: 0.839 (p < 0.01) for the right and left PFC, between [O2Hb]c and the SARA stance score respectively r: 0.893 (p < 0.01) and r: 0.832 (p < 0.01). Conclusions: During over ground gait PFC is bilaterally activated in patients with severe chronic ataxia. These findings may be associated with compensatory mechanisms which are involved in severe conditions when other nervous centers controlling balance are functionally not efficient.     

Progression of coronary artery calcium in men affected by human immunodeficiency virus infection

Cardiovascular risk is increased in HIV infected patients. We assessed progression of coronary artery calcium (CAC) in patients with HIV infection to identify factors that may help explain progression of atherosclerosis. Prospective, observational study of 132 HIV-infected men receiving chronic antiretroviral therapy (ART); we measured traditional atherosclerosis risk factors and assessed progression of CAC on sequential 64-slice CT scans at an average interval of 11 months (range 6-36). CAC score progression was defined as absolute and percentage change from baseline. During follow-up 45 patients (34%) showed absolute progression of CAC and 34 of them showed >15% yearly progression, a threshold previously associated with a high risk of myocardial infarction. Age, LDL cholesterol, visceral abdominal fat and current T-helper (CD4+) cell count were significantly associated with absolute CAC progression. Progression of subclinical atherosclerosis in HIV patients is associated with traditional coronary risk factors as well as HIV related factors such as the CD4+ cell count. Therefore, immunologic perturbations secondary to HIV infection may contribute to atherosclerosis progression.     

Ictal haemodynamic changes in a patient affected by “subtle” Epilepsia Partialis Continua

We report on a 64 year-old woman presenting with Epilepsia Partialis Continua (EPC) affecting the left hand since the age of 24 without neurological deficit. Structural MRI showed a region of focal cortical dysplasia (FCD) over the right central gyrus and lesions in the mesial frontal and occipital cortex secondary to perinatal hypoxic injury. Ictal spike haemodynamic mapping using simultaneous EEG-fMRI revealed significant BOLD signal changes prominent in the region of FCD (larger cluster), occipital cortex (global statistical maximum), prefrontal cortex and cerebellum. The cluster over FCD was in good agreement with the result of EEG source analysis.Our findings provide an interesting illustration of the ability of EEG-fMRI to reveal epileptogenic networks confirming the intrinsic epileptogenic properties of dysplastic neurons.