Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.

Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial.

CONTEXT: Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. OBJECTIVE: To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006. INTERVENTION: Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. MAIN OUTCOME MEASURES: The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. RESULTS: Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. CONCLUSION: In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056563.

Spinal muscular atrophy: classification, diagnosis, management, pathogenesis, and future research directions.

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder that affects the motor neurons responsible for movement of the proximal muscles of the trunk and body. To date, the disease can be classified into 3 main categories based on severity and age of onset. During the October 18th symposium held in Pittsburgh, Pennsylvania, researchers met to (1) describe current diagnostic strategies, (2) discuss recent thoughts on pathogenesis, (3) review current therapies and clinical trials, and (4) define future research directions. In her opening remarks, Dr Story Landis, director of the National Institute of Neurological Disorders and Stroke, emphasized the degree to which the Neurobiology of Disease in Children conference series has broadened awareness of the many rare diseases affecting children, not only through the advancement of research but also by educating practitioners about diagnostic strategies. Dr Landis also discussed the role this conference may play in fostering research that seeks to develop a single mechanism of therapy for spinal muscular atrophy. She also discussed the current funding situation at the National Institutes of Health and addressed the crucial function of volunteer research organizations that sponsor research in further improving management of this condition. This article summarizes the presentations and includes the verbatim edited transcript of question-and-answer sessions.

Teaching old drugs new tricks. Meeting of the Neurodegeneration Drug Screening Consortium, 7-8 April 2002, Washington, DC, USA.

Meeting of the Neurodegeneration Drug Screening Consortium, held on 7-8 April 2002, Washington, DC, USA.

Commonalities and challenges in the development of clinical trial measures in neurology.

As neurologists and neuroscientists, we are trained to evaluate disorders of the nervous system by thinking systematically. Clinically, we think in terms of cognition, behavior, motor function, sensation, balance and co-ordination, and autonomic system function. But when we assess symptoms of neurological disorders for the purpose of drug development, we tend to create disease-specific outcome measures, often using a variety of methods to assess the same types of dysfunction in overlapping, related disorders. To begin to explore the potential to simplify and harmonize the assessment of dysfunction across neurological disorders, a symposium, entitled, "Commonalities in the Development of Outcome Measures in Neurology" was held at the 16th annual meeting of the American Society for Experimental NeuroTherapeutics (ASENT), in February 2014. This paper summarizes the presentations at the symposium. The authors hope that readers will begin to view Clinical Outcome Assessment (COA) development in a new light. We hope that in presenting this material, we will stimulate discussions and collaborations across disease areas to develop common concepts of neurological COA development and construction.

Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold.

Abuse of ethanol is a major risk factor in medicine, in part because of its widespread effect on the activity of the central nervous system, including behavior, pain, and temperature sensation. Uncoupling protein 2 (UCP2) is a mitochondrial protonophore that regulates cellular energy homeostasis. Its expression in mitochondria of axons and axon terminals of basal forebrain areas suggests that UCP2 may be involved in the regulation of complex neuronal responses to ethanol. We employed a paradigm in which acute exposure to ethanol induces tolerance and altered pain and temperature sensation. In UCP2 overexpressing mice, sensitivity to ethanol was decreased compared to that of wild-type animals, while UCP2 knockouts had increased ethanol sensitivity. In addition, UCP2 expression was inversely correlated with the impairment of pain and temperature sensation induced by ethanol. Taken together, these results indicate that UCP2, a mitochondrial uncoupling protein previously associated with peripheral energy expenditure, is involved in the mediation of acute ethanol exposure on the central nervous system. Enhancement of UCP2 activation after acute alcohol consumption might decrease the time of recovery from intoxication, whereas UCP2 inhibition might decrease the tolerance to ethanol.

Neuroscience networking: linking discovery to drugs.

Discoveries in the pre-clinical neurosciences have set the stage for bringing new therapies to patients affected by neurological disorders. The National lnstitute of Neurological Disorders and Stroke (NINDS) is dedicated to promoting the development of new therapies through its funding programs that range from basic neuroscience to translational research and finally clinical research to test the most promising new therapies in patients. In an effort to accelerate the translation of new discoveries to clinical practice, NINDS is piloting novel organizational strategies. In translational research, NINDS is taking the lead on the establishment of a 'virtual pharma' structure, through which researchers will partner with the NIH to accelerate the progress of drug development from early hit discovery through phase 1 clinical trials. In clinical research, the new Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) aims to promote the efficient implementation of scientifically sound, biomarker-informed phase 2 clinical trials that can be initiated by academic or industry investigators.

Primary and secondary drug screening assays for Friedreich ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix for the assembly of iron-sulfur clusters (ISCs), which are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain (ETC). Decreased expression of frataxin or the yeast frataxin orthologue, Yfh1p, is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute to mitochondrial dysfunction. Using yeast depleted of Yfh1p, a high-throughput screening (HTS) assay was developed in which mitochondrial function was monitored by reduction of the tetrazolium dye WST-1 in a growth medium with a respiration-only carbon source. Of 101 200 compounds screened, 302 were identified that effectively rescue mitochondrial function. To confirm activities in mammalian cells and begin understanding mechanisms of action, secondary screening assays were developed using murine C2C12 cells and yeast mutants lacking specific complexes of the ETC, respectively. The compounds identified in this study have potential relevance for other neurodegenerative disorders associated with mitochondrial dysfunction, such as Parkinson disease.