CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 14, Issue 5, 2015

Uric acid has been associated as a risk factor for cardiovascular disease. Recently, however, there is growing evidence that uric acid plays a role as antioxidant in the brain. In cognitive dysfunction, vascular and oxidative stress mechanisms play a role, but the link remains unknown. Therefore, we investigated the link between serum uric acid-levels and cognitive function in 62 elderly subjects. The statistical analysis was adjusted to age, sex and cardiovascular risk factors. Here, we found that lower serum uric acid levels are linked to cognitive dysfunction. In a Mexican population, higher levels of uric acid are associated with a decreased risk of dementia.

Stroke is one of the most common conditions requiring rehabilitation, and its motor impairments are a major cause of permanent disability. Hemiparesis is observed by 80% of the patients after acute stroke. Neuroimaging studies showed that real and imagined movements have similarities regarding brain activation, supplying evidence that those similarities are based on the same process. Within this context, the combination of mental practice (MP) with physical and occupational therapy appears to be a natural complement based on neurorehabilitation concepts. Our study seeks to investigate if MP for stroke rehabilitation of upper limbs is an effective adjunct therapy. PubMed (Medline), ISI knowledge (Institute for Scientific Information) and SciELO (Scientific Electronic Library) were terminated on 20 February 2015. Data were collected on variables as follows: sample size, type of supervision, configuration of mental practice, setting the physical practice (intensity, number of sets and repetitions, duration of contractions, rest interval between sets, weekly and total duration), measures of sensorimotor deficits used in the main studies and significant results. Random effects models were used that take into account the variance within and between studies. Seven articles were selected. As there was no statistically significant difference between the two groups (MP vs control), showed a – 0.6 (95% CI: –1.27 to 0.04), for upper limb motor restoration after stroke. The present meta-analysis concluded that MP is not effective as adjunct therapeutic strategy for upper limb motor restoration after stroke.

Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer’s disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.

Traumatic brain injury (TBI) is a leading cause of death and disability for which there is currently no effective drug therapy available. Because drugs targeting a single TBI pathological pathway have failed to show clinical efficacy to date, pleiotropic agents with effects on multiple mechanisms of secondary brain damage could represent an effective option to improve brain recovery and clinical outcome in TBI patients. In this multicenter retrospective study, we investigated severity-related efficacy and safety of the add-on therapy with two concentrations (20 ml/day or 30 ml/day) of Cerebrolysin (EVER Neuro Pharma, Austria) in TBI patients. Adjunctive treatment with Cerrebrolysin started within 48 hours after TBI and clinical outcomes were ranked according to the Glasgow Outcome Scale and the Modified Rankin Disability Score at 10 and 30 days post-TBI. Analyses of efficacy were performed separately for subgroups of patients with mild, moderate or severe TBI according to Glasgow Coma Scale scores at admission. Compared to standard medical care alone (control group), both doses of Cerebrolysin were associated with improved clinical outcome scores at 10 days post-TBI in mild patients and at 10 and 30 days in moderate and severe cases. A dose-dependent effect of Cerebrolysin on TBI recovery was supported by the dose-related differences and the significant correlations with treatment duration observed for outcome measures. The safety and tolerability of Cerebrolysin in TBI patients was very good. In conclusion, the results of this large retrospective study revealed that early Cerebrolysin treatment is safe and is associated to improved TBI outcome.

Medulloblastoma, a tumor of the cerebellum, is the most common pediatric central nervous system malignancy. These tumors are etiologically linked to mutations in the Sonic hedgehog (Shh) pathway, which signals through the primary, non-motile cilium. The growth of these aggressive tumors relies on self-renewal of tumor-propagating cells known as cancer stem cells (CSCs). Previous reports have implicated CD133-expressing cells as CSCs in brain tumors, while those expressing CD15 have been shown to propagate medulloblastoma. Here, we demonstrate that CD133+ and CD15+ cells are distinct medulloblastoma populations. CD15+ cells comprise approximately 0.5-1% of total human medulloblastoma cells, display CSC properties in culture and are detected in the Smoothened A1 transgenic mouse model of medulloblastoma. Additionally, we report on a medulloblastoma patient with enriched CD15+ cells in recurrent vs primary medulloblastoma. We also demonstrate that human medulloblastoma cells critically rely on establishment of primary cilia to drive Shh-mediated cell division. Primary cilia are found in external granule cells of human fetal cerebellum and in 12/14 medulloblastoma samples. Yet, CD15+ medulloblastoma cells lack primary cilia, suggesting that this CSC population signals independently of Shh. These results are important when considering the effects of current and prospective treatment modalities on medulloblastoma CSC populations.

Transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein (TARP) γ−8 is an auxiliary protein associated with some AMPA receptors. Most strikingly, AMPA receptors associated with this TARP have a relatively high localization in the hippocampus. TARP γ−8 also modifies the pharmacology and trafficking of AMPA receptors. However, to date there is little understanding of the biological significance of this auxiliary protein. In the present set of studies we provide a characterization of the differential pharmacology and behavioral consequences of deletion of TARP γ−8 by comparing the wild type (WT) and γ−8 -/- (knock-out, KO) mouse. KO mice were mildly hyperactive in a locomotor arena but not in other environments compared to WT mice. Additionally, the KO mice demonstrated enhanced locomotor stimulatory effects of both d-amphetamine and phencyclidine. Marble-burying and digging behaviors were dramatically reduced in KO mice. In another assay that can detect anxiety-like phenotypes, the elevated plus maze, no differences were observed in overall movement or open arm entries. In the forced-swim assay, KO mice displayed decreases in immobility time like the antidepressant imipramine and the AMPA receptor potentiator, LY392098. In KO mice, the antidepressant-like effects of LY392098 were prevented whereas the effects of imipramine were unaffected. Convulsions were induced by pentylenetetrazole, N-methyl-D-aspartate, and by kainic acid. However, in KO mice, kainic acid produced less tonic convulsions and lethality. KO mice had reduced levels of norepinephrine in hippocampus and cerebellum but not in hypothalamus or prefrontal cortex, decreased levels of cAMP in hippocampus, and increased levels of acetylcholine in the hypothalamus and prefrontal cortex. KO mice displayed decreased turnover of dopamine and increased histamine turnover in multiple brain areas In contrast, serotonin and its metabolites were not significantly affected by deletion of the γ−8 protein. Of a large panel of plasma lipids, only two monoacylglycerols (1OG and 2OG) were marginally but nonsignificantly altered in WT vs KO mice. Overall, the data suggest genetic inactivation of this specific population of AMPA receptors results in modest changes in behavior characterized by a mild hyperactivity which is condition dependent and a marked reduction in digging and burying behaviors. Despite deletion of TARP γ−8, chemoconvulsants were still active. Consistent with their predicted pharmacological actions, the convulsant effects of kainate and the antidepressant-like effects of an AMPA receptor potentiator (both acting upon AMPA receptors) were reduced or absent in KO mice.

Objective: It is our aim to elaborate on the new developments in regard to the respiratory subtype (RS) of panic disorder (PD) since it was first described. We will present psychopathological features, diagnostic criteria, genetic and physiopathological hypotheses, as well as therapeutic and prognostic characteristics. Method: Two searches were performed in the Thomson Reuters Web of Knowledge (http://wokinfo.com/): 1 - search terms: “panic disorder” AND (“respiratory symptom” OR “respiratory symptoms” OR “respiratory subtype” OR “respiratory panic” OR “cardiorespiratory”); 2 - all articles citing Briggs and colleagues’ 1993 article “Subtyping of Panic Disorder by Symptom Profile” (Br J Psychiatry 1993;163: 201-9). Only those articles involving human subjects and written English were included. Results: In comparison with patients of the non-respiratory subtype (NRS), RS patients showed greater familial history of PD, and higher comorbidity rates for anxiety disorders and depressive disorders. These patients were also more sensitive to CO2, hyperventilation and caffeine. Conclusion: Certain characteristics, such as heightened sensitivity to CO2 and the higher incidence of a family history of PD, clearly distinguished the Respiratory Subtype patients from the Non-Respiratory. Nonetheless, some studies failed to demonstrate differential responses to pharmacological treatment and CBT across the subtypes. RS patients seem to respond faster than NRS to pharmacological treatment with antidepressants and benzodiazepines, but more studies are needed to confirm this finding.

A significant number of laboratories observed that poly (ADP-ribose) polymerase (PARP) inhibitors, administered a few hours after ischemic or traumatic brain injury, may drastically reduce the subsequent neurological damage. It has also been shown that PARP inhibitors, administered for 24 hours to rats with permanent middle cerebral artery occlusion (MCAO), may reduce the number of dying neurons for a long period after surgery, thus suggesting that these agents could reduce the delayed brain damage and the neurological and cognitive impairment (dementia) frequently observed a few months after a stroke. In organotypic hippocampal slices exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), an alkylating agent able to activate PARP, a selective and delayed degeneration of the CA1 pyramidal cells which was anatomically similar to that observed after a short period of oxygen and glucose deprivation (OGD) has been described. Biochemical and electrophysiological approaches showed that MNNG exposure caused an increased expression and function of the calcium permeable α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) channels in the CA1 but not in the CA3 hippocampal region. PARP inhibitors prevented this increase and reduced CA1 cell death. The AMPA receptor antagonist 2,3-dihydroxy-6- nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione or the selective Ca2+ permeable AMPA channel blocker 1-Naphthyl acetyl spermine (NASPM), also reduced the MNNG-induced CA1 pyramidal cell death. Since activation of PARP-1 facilitate the expression of Ca2+ permeable channels and the subsequent delayed cell death, PARP inhibitors administered a few hours after a stroke may not only reduce the early post-ischemic brain damage but also the late neuronal death frequently occurring after severe stroke.

Major depressive disorder (MDD) is a serious mental illness that affects millions of people worldwide. There is now compelling evidence that the neuronal nicotinic acetylcholine receptors (nAChRs) play an important role in MDD and co-morbid alcohol or nicotine addiction. As a result, there has been growing interest for the treatment of MDD and co-morbid alcohol or nicotine use disorder by targeting nAChRs. Emerging evidence suggests that specific ligands that act at nAChRs significantly reduce depression-like behaviors in preclinical models that mimic MDD and co-morbid alcohol or nicotine use disorder. In this review, the pharmacological efficacy of nAChR ligands, such as mecamylamine, lobeline, cytisine, sazetidine-A, and others will be discussed. Overall, findings from preclinical and clinical studies included here suggest that the nAChR ligands may be of potential benefit in reducing MDD symptoms and that may aid in the prevention and treatment of MDD and co-morbid alcohol or nicotine use disorder.

Numerous studies have deciphered the importance of Cyclophilin D (CypD/ peptidyl prolyl cis-trans isomerase F) in the formation and regulation of mitochondrial permeability transition pore (MPTP), implicated in the cell death mechanisms in various neurological diseases. Decrease in the ATP and increase in the calcium levels are the most common aftermath consequences that are observed in these diseases. Increased calcium level leads to the persistent opening of MPTP and cell death, which is mediated by CypD. However, the underlying mechanisms that contribute to the abnormal calcium homeostasis in different diseases remain elusive. In this review, we attempted to connect the disruption of mitochondrial bioenergetics with abnormal calcium levels and MPTP. Further, various proteins that interact with the CypD and the subsequent consequences have been described. All the cell death pathways in various neurological disorders merge at CypD, which acts as a key regulatory protein in cellular demise. Agents inhibiting CypD may have a therapeutic potential for treating neurological disorders such as Alzheimer’s disease, Parkinson’s disease and cerebral ischemia. Further, the knowledge regarding the pathophysiological processes involved in CypD-regulated MPTP and cell death would assist in battling with these diseases.

Migraine and neuropathic pain are common causes of chronic pain. The exact pathomechanism has not been fully clarified for either disorder, but their pathophysiological backgrounds involve several similar mechanisms. Peripheral sensitization occurs in the neuronal elements of the dorsal root ganglion or the trigeminal ganglion, while central sensitization appears in the second-order neurons in the dorsal horn of the spinal cord or the trigeminal nucleus caudalis. Central neuronal hyperexcitability has been implicated in both disorders, and the emerging evidence suggests alterations in the glutamatergic neurotransmission and N-methyl-D-aspartate-receptor activation. Migraine and neuropathic pain additionally share certain clinical features, such as enhanced sensitivity to sensory stimuli and cutaneous allodynia. The pharmacotherapy of both diseases is often challenging, but several antiepileptic drugs that target hyperexcitability are beneficial for both migraine and neuropathic pain. Kynurenine pathway metabolites are capable of influencing the glutamate receptors, and might therefore be novel candidates for future drug development.

Results from amyotrophic lateral sclerosis (ALS) patients and pre-clinical studies strongly suggest that systemic and CNS-intrinsic immune activation plays a central role in ALS pathogenesis. Microglial cells are emerging in this context as master regulators with a bi-functional role in the progression of the pathological response. They foster a pro-inflammatory setting through the production of cytotoxic cytokines and chemokines (M1 phenotype), after an aborted effort to sustain an anti-inflammatory environment for motor neurons through the release of beneficial cytokines and growth factors (M2 phenotype). In this review, we gather information meant to propose that histamine and ATP, which are released from mast cells, microglia and damaged neurons at sites of injury where they function as transmitters, have to be considered as new players in the ALS neuroinflammatory arena. After all, abnormal histamine and ATP signalling in the brain are already documented in neurodegenerative/neuroinflammatory conditions such as multiple sclerosis, Alzheimer and Parkinson's disease and, at present, histamine- as well as ATP-related compounds are in clinical trial for these same pathologies. Concerning ALS, while emerging data are now available about purinergic mechanisms, the involvement of histamine is basically unexplored. The circumstantial evidence that we present here thus constitutes a solid background for formulating novel hypotheses, stimulating a scientific debate and, most of all, inspiring future research. We deem that a new potential role of histamine in the setting of ALS neuroinflammation might find a fertile ground where to thrive. ALS is still a disease without a cure: why not to play with a new kid on the block?