Hippocampal volume and vasculature before and after exercise in treatment-resistant schizophrenia.

BACKGROUND: Schizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia. METHODS: Seventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ±â€¯9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks. RESULTS: At follow-up, symptom severity scores (t(16) = -16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = -2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = -2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = -2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores. CONCLUSIONS: Adjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise. STUDY REGISTRATION: Clinical Trials.govNCT01392885.

Brain cooling during transient focal ischemia provides complete neuroprotection.

A review of the effects of reducing brain temperature on ischemic brain injury is presented together with original data describing the systematic evaluation of the effects of brain cooling on brain injury produced by transient focal ischemia. Male spontaneously hypertensive rate were subjected to transient middle cerebral artery occlusion (TMCAO; 80, 120 or 160 min) followed by 24 h of reperfusion. During TMCAO, the exposed skull was bathed with isotonic saline at various temperatures to control skull and deeper brain temperatures. Rectal temperature was always constant at 37 degrees C. Initial studies indicated that skull temperature was decreased significantly (i.e. to 32-33 degrees C) just as a consequence of surgical exposure of the artery. Subsequent studies indicated that maintaining skull temperature at 37 degrees C compared to 32 degrees C significantly (p < 0.05) increased the infarct size following 120 or 160 min TMCAO. In other studies, 80 min TMCAO was held constant, but deeper brain temperature could be varied by regulating skull temperature at different levels. At 36-38 degrees C brain temperature, infarct volumes of 102 +/- 10 to 91 +/- 9 mm3 occurred following TMCAO. However, at a brain temperature of 34 degrees C, a significantly (p < 0.05) reduced infarct volume of 37 +/- 10 mm3 was observed. Absolutely no brain infarction was observed if the brain was cooled to 29 degrees C during TMCAO. Middle cerebral artery exposure and maintaining brain temperature at 37 degrees C without artery occlusion did not produce any cerebral injury. These data indicated the importance of controlling brain temperature in cerebral ischemia and that reducing brain temperature during ischemia produces a brain temperature-related decrease in focal ischemic damage. Brain cooling of 3 degrees C and 8 degrees C can provide dramatic and complete, respectively, neuroprotection from transient focal ischemia. Multiple mechanisms for reduced brain temperature-induced neuroprotection have been identified and include reduced metabolic rate and energy depletion, decreased excitatory transmitter release, reduced alterations in ion flux, and reduced vascular permeability, edema, and blood-brain barrier disruption. Cerebral hypothermia is clearly the most potent therapeutic approach to reducing experimental ischemic brain injury identified to date, and this is emphasized by the present data which demonstrate complete neuroprotection in transient focal stroke. Certainly all available information warrants the evaluation of brain cooling for potential implementation in the treatment of human stroke.

Genetic hypertension and increased susceptibility to cerebral ischemia.

A review of the sensitivity of genetically hypertensive rats to cerebral ischemia was presented together with original data describing the systematic comparison of the effects of focal ischemia (permanent and temporary with reperfusion) performed in hypertensive and normotensive rats (i.e., blood pressures verified in conscious instrumented rats). Microsurgical techniques were used to isolate and occlude the middle cerebral artery (MCAO) of spontaneously hypertensive (SHR), Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats at the level of the inferior cerebral vein. Following permanent (24 h) MCAO, persistent and similar decreases in local microvascular perfusion (i.e., to 15.6 +/- 1.7% of pre-MCAO levels) were verified in the primary ischemic zone of the cortex for all strains using Laser-Doppler flowmetry. A contralateral hemiplegia that occurred following MCAO, evidenced by forelimb flexion and muscle weakness, was greater in SHR (neurological grade = 2.0 +/- 0.1) than SD (1.0 +/- 0.4) or WKY (0.7 +/- 0.4) rats (N = 7-9, p less than 0.05). SHR also exhibited sensory motor deficits following MCAO compared to sham-operation, with decreased normal placement response of the hindlimb (% normal = 20 vs. 83, N = 23-30, p decreased rota-rod (41 +/- 7 vs. 126 +/- 19 on rod, N = 10-15, p less than 0.05) and balance beam (25 +/- 5 vs. 116 +/- 29 s on beam, N = 5-7, p less than 0.05) performance. However, an index of general motor activity was not affected by permanent MCAO. Triphenyltetrazolium-stained forebrain tissue analyzed by planimetry revealed a significantly larger and more consistent cortical infarction in SHR (hemispheric infarction = 27.9 +/- 1.5%) compared to SD (15.4 +/- 4.1%) and WKY (4.0 +/- 2.4%) rats (N = 7-9, p less than 0.05), occupying predominantly the frontal and parietal areas. Also, a significant degree of ipsilateral hemispheric swelling (4.6 +/- 0.9%, N = 7-9, p less than 0.05) and increased brain water content (78.4 +/- 0.3% to 80.4 +/- 0.2%, N = 8-9, p less than 0.05) was identified in SHR that was not observed in SD or WKY rats. A novel model of temporary MCAO also was evaluated in the hypertensive and normotensive rat strains. Initially, the effect of increasing MCAO-time followed by 24 h reperfusion in SHR was studied. During temporary MCAO (20 to 300 min), persistent and stable decreases in local microvascular perfusion (i.e., to 15-20% of pre-MCAO levels) were verified in the primary ischemic zones of the cortex.(ABSTRACT TRUNCATED AT 400 WORDS)

Endothelin levels increase in rat focal and global ischemia.

Endothelin-1, a peptide exhibiting extremely potent cerebral vasoactive properties, is elevated in the cerebrospinal fluid after hemorrhagic stroke and implicated in cerebral vasospasm. The purpose of this study was to determine changes in endothelin in ischemic rat brain by assaying endothelin tissue and extracellular levels. Immunoreactive endothelin levels in ischemic brain tissue following permanent or transient focal ischemia produced by middle cerebral artery occlusion was determined. In addition, endothelin levels were assayed in striatal extracellular fluid collected by microdialysis before, during, and after global ischemia produced by two-vessel occlusion combined with hypotension. Twenty-four hours after the onset of permanent middle cerebral artery occlusion, the ischemic cortex level (0.58 +/- 0.27 fmol/mg protein) of immunoreactive endothelin was significantly (p < 0.05) increased, by 100%, over that in the nonischemic cortex (0.29 +/- 0.13 fmol/mg protein). Transient artery occlusion for 80 min with reperfusion for 24 h also resulted in a similar significant (p < 0.05) increase, 78%, in immunoreactive endothelin in the ischemic zone. Global forebrain ischemia significantly (p < 0.05) increased the level of immunoreactive endothelin collected in striatal microdialysis perfusate, from a basal level of 14.6 +/- 6.7 to 26.5 +/- 7.7 and 26.2 +/- 7.4 amol/microliters (i.e. 82 and 79%). These changes reflect the relative picomolar extracellular concentration increases during ischemia and following reperfusion, respectively. This is the first demonstration of elevated levels of endothelin in focal ischemic tissue and in the extracellular fluid in global ischemia and suggests a role of the peptide in ischemic and postischemic derangements of cerebral vascular function and tissue injury.

Trimethyltin encephalopathy.

A chemistry student was acutely exposed to vapors of an organotin compound. Seventy-two hours later, he exhibited delirium, spatial disorientation, perseveration, inappropriate affect, and memory defects. Five months later, he experienced episodes of complex partial seizures, which continue to require anticonvulsant medication after 7 years. Trimethyltin was identified in blood and urine samples taken 17 days after the accident; the blood level of trimethyltin was elevated 35 days after exposure. Serial electroencephalograms showed persistent left temporal paroxysmal epileptogenic potentials. Serial neuropsychological tests revealed persistent memory defects, cognitive dysfunction, and dysphoria 4 years after exposure. We review acute, resolving, and long-term residual neurotoxic effects of trimethyltin in man. We describe detailed clinical observations, serial neuropsychological test results, electroencephalographic findings, and exposure data in this patient, confirming the limbic system effects of trimethyltin and relating them to the known histopathologic pattern of this condition.

The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort.

OBJECTIVES: To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. DESIGN: From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. SETTING: A community-based center for epidemiological research. PARTICIPANTS: Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. MAIN OUTCOME MEASURE: Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. RESULTS: Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. CONCLUSIONS: The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.

Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep.

Postmortem studies of patients with progressive supranuclear palsy (PSP) have demonstrated loss of cholinergic neurons in the striatum, nucleus basalis of Meynert, and the pedunculopontine nucleus. These findings suggest that cholinergic drugs might be an effective treatment for this disease. We studied the efficacy of RS-86, a direct cholinergic agonist, upon motor abilities, eye movements, and psychometric performance in 10 patients with PSP during a 9-week placebo-controlled, double-blinded, crossover trial. Glycopyrrolate, a peripheral anticholinergic drug, was given throughout the trial to minimize cholinergic side effects. We used changes in rapid eye movement (REM) sleep to assess the degree of cholinergic activation achieved by treatment. Despite the enhancement of cholinergic activity in the CNS as indicated by increases in REM sleep latency and REM sleep time, RS-86 did not improve motor signs, eye movements, or cognition. Pharmacologic replacement of the cholinergic deficits in PSP does not result in significant clinical benefit.

Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.

Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.

Role of the neurologist in hazard identification and risk assessment.

This review describes strategies used by a clinical neurologist in the investigation of neurotoxic disease. It emphasizes the need for a high level of suspicion that environmental substances are capable of producing impairments in neurologic and neurobehavioral functions. Because of the difficulties in differentiating neurotoxic from nonneurotoxic disease when presented with common neurological symptoms, it is necessary to rely upon corroborative evidence from past medical records, work and environmental histories, and exposure data, as well as detailed neurological examinations, to reach a conclusion about causation. Sensitive electrophysiologic and neuropsychologic test batteries are useful in identifying subclinical impairments and in providing objective confirmation of abnormalities in the central and peripheral nervous systems. Combining scientific and epidemiologic information with experience and clinical judgment, these sources of information are used in the formulation of a clinical diagnosis. When many patients among a group of people are exposed to neurotoxicants, the effects of the exposure may vary from one to another because of differences in susceptibility, duration of exposure and dosage of neurotoxicant, and other possible risk factors. Group statistics may obscure a significant effect for the larger group, despite clinically obvious effects in an individual. The neurologist applies clinical skills and refers to the accumulated neurotoxicologic literature as a frame of reference to make a diagnosis about an individual patient or a group of patients who have been exposed to particular neurotoxicants. The Boston University Environmental Neurology Assessment (BUENA) is a scheme that attempts to combine epidemiologic methodology and clinical approaches to detect effects of neurotoxic exposure. The advantages and limitations of such a strategy are discussed.

Neurobehavioral epidemiology: application in risk assessment.

Neurobehavioral epidemiology may contribute information to risk assessment in relation to a) characterization of neurotoxicity and its time course; b) the dose-effect relationship; c) the dose-response relationship; and d) predisposing factors. The quality of this information relies on the validity of the exposure data, the validity and sensitivity of neurobehavioral function tests, and the degree to which sources of bias are controlled. With epidemiologic studies of methylmercury-associated neurotoxicity as an example, the field of research involves numerous uncertainties that should be taken into account in the risk assessment process.

Methylmercury neurotoxicity in Amazonian children downstream from gold mining.

In widespread informal gold mining in the Amazon Basin, mercury is used to capture the gold particles as amalgam. Releases of mercury to the environment have resulted in the contamination of freshwater fish with methylmercury. In four comparable Amazonian communities, we examined 351 of 420 eligible children between 7 and 12 years of age. In three Tapajós villages with the highest exposures, more than 80% of 246 children had hair-mercury concentrations above 10 microg/g, a limit above which adverse effects on brain development are likely to occur. Neuropsychological tests of motor function, attention, and visuospatial performance showed decrements associated with the hair-mercury concentrations. Especially on the Santa Ana form board and the Stanford-Binet copying tests, similar associations were also apparent in the 105 children from the village with the lowest exposures, where all but two children had hair-mercury concentrations below 10 microg/g. Although average exposure levels may not have changed during recent years, prenatal exposure levels are unknown, and exact dose relationships cannot be generated from this cross-sectional study. However, the current mercury pollution seems sufficiently severe to cause adverse effects on brain development.

The chemical induction of PR (b) proteins and resistance to TMV infection in tobacco.

Aspirin injected into Xanthi-nc tobacco leaves induces the production of PR protein and resistance to TMV. The concentration of PR protein and resistance increases with increasing aspirin concentration, up to a plateau. 2-Thiouracil and dioxohexahydrotriazine also induce PR protein when injected into tobacco leaves. Barium and manganese salts induced PR protein, but those of eight other cations did not. Certain salts were phytotoxic but did not induce PR protein, confirming that the production of PR protein is not a non-specific stress response.

Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.

BACKGROUND: Most US troops returned home from the Persian Gulf War (PGW) by Spring 1991 and many began reporting increased health symptoms and medical problems soon after. This investigation examines the relationships between several Gulf-service environmental exposures and health symptom reporting, and the role of traumatic psychological stress on the exposure-health symptom relationships. METHODS: Stratified, random samples of two cohorts of PGW veterans, from the New England area (n = 220) and from the New Orleans area (n = 71), were selected from larger cohorts being followed longitudinally since arrival home from the Gulf. A group of PGW-era veterans deployed to Germany (n = 50) served as a comparison group. The study protocol included questionnaires, a neuropsychological test battery, an environmental interview, and psychological diagnostic interviews. This report focuses on self-reported health symptoms and exposures of participants who completed a 52-item health symptom checklist and a checklist of environmental exposures. RESULTS: The prevalence of reported symptoms was greater in both Persian Gulf-deployed cohorts compared to the Germany cohort. Analyses of the body-system symptom scores (BSS), weighted to account for sampling design, and adjusted by age, sex, and education, indicated that Persian Gulf-deployed veterans were more likely to report neurological, pulmonary, gastrointestinal, cardiac, dermatological, musculoskeletal, psychological and neuropsychological system symptoms than Germany veterans. Using a priori hypotheses about the toxicant effects of exposure to specific toxicants, the relationships between self-reported exposures and body-system symptom groupings were examined through multiple regression analyses, controlling for war-zone exposure and post-traumatic stress disorder (PTSD). Self-reported exposures to pesticides, debris from Scuds, chemical and biological warfare (CBW) agents, and smoke from tent heaters each were significantly related to increased reporting of specific predicted BSS groupings. CONCLUSIONS: Veterans deployed to the Persian Gulf have higher self-reported prevalence of health symptoms compared to PGW veterans who were deployed only as far as Germany. Several Gulf-service environmental exposures are associated with increased health symptom reporting involving predicted body-systems, after adjusting for war-zone stressor exposures and PTSD.

Influenza vaccination in community elderly. A controlled trial of postcard reminders.

Available strategies to increase influenza vaccination rates in the elderly have not been tested in the private sector where most elderly receive care. We performed a randomized controlled trial of a postcard reminder in the three private general internal medicine practices. The observed vaccination rates of 55% in experimental patients (N = 262) and 54% in control patients (N = 278) were similar, though much higher than estimated national rates of 20%. The data indicated that the baseline (control group) vaccination rate was high probably because study participants were exposed to many community vaccination cues, separate from the study cue. That vaccination rates were not higher after additional exposure to the study cue suggests that a "ceiling effect" occurred. Including 70 patients not randomized into the trial because they received flu shots prior to randomization, the vaccination rate in patients who had a clinic visit during autumn months was 75% compared to a rate of 52% in patients not visiting the clinic (P less than .001). Our results suggest that vaccination rates can be considerably higher in the private sector than those reported in the past, and that both vaccination cues and direct patient contact appear important to promote vaccination. This and other studies suggest that traditional cues may have a ceiling effect, yielding vaccination rates no higher than 55 to 65%; further increases in rates will require other approaches.

A computer program to record technical data in leukapheresis and plateletpheresis procedures.

A computer program for the recording of data and calculation of results from leukapheresis and plateletpheresis procedures is described. It provides a printout of cell yields and other results for each procedure, as well as an updated list of donors and phereses. The data are kept on tape, accessible for periodic statistical analysis. While primarily set up for use with Haemonetics (intermittent-flow centrifugation) equipment, the program is adaptable for other systems.

Neuron-specific enolase increases in cerebral and systemic circulation following focal ischemia.

Neuron-specific enolase (NSE) is an isoform of the glycolytic enzyme, enolase, and is found in neurons and neuroendocrine cells. We evaluated cerebral immunohistologic and plasma changes in NSE in rats from 2 h to 15 days following permanent or transient middle cerebral artery occlusion (MCAO). At 1-2 days post-MCAO, loss of NSE immunofluorescence from within neurons to the extracellular space was observed in the infarcted areas of all MCAO animals. NSE also was identified intravascularly throughout the brain following MCAO. NSE in plasma was determined by a specific radioimmunoassay. Plasma NSE following permanent or transient MCAO was increased significantly from that observed in controls (2.8 +/- 0.3 ng/ml) beginning at 2 h and persisting for 2.5 days post-MCAO (maximum levels of 8.8 +/- 0.9 to 9.6 +/- 0.5 ng/ml after 6-12 h; P < 0.05, n = 4-9). Quantified contralateral forelimb and hindlimb neurological deficits in these animals were significant and persisted for at least 15 days following MCAO but were not observed following sham surgery. These data suggest that MCAO-induced cortical infarction and neurological dysfunction is associated with neuronal depletion and vascular redistribution of brain NSE resulting in a measurable increase in plasma NSE. Such diffusion of NSE into the cerebral vasculature and systemic circulation from ischemic tissue can be expected to serve as a marker for the incidence of cerebral damage in acute and chronic ischemic brain infarcts.

Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27.

We have established a focal preconditioning (PC) paradigm that produces significant and prolonged ischemic tolerance (IT) of the brain to subsequent permanent middle cerebral artery occlusion (MCAO). PC using 10 min of MCAO induces brain tolerance at 1-7 days of reperfusion that requires active protein synthesis. The protective protein(s) involved are unknown. In these studies the increased transcription and translation of the inducible 70-kDa heat shock protein (Hsp70) and the 27-kDa heat shock protein (Hsp27), and astrogliosis/glial fibrillary acidic protein (GFAP) were determined by Northern analysis and immunohistochemistry following PC. Cellular localization of proteins was determined by double labeling. PC produced no brain injury but did increase Hsp70 mRNA transiently at 6 h and increased Hsp27 mRNA later at 24 h for at least 5 days. Protein expression induced by PC exhibited a similar profile. Hsp70 protein was primarily expressed in neurons from 1 to 5 days post-PC throughout the PC cortex. Hsp27 protein expression was initiated later for a much longer period of time. A remarkable astroglyosis was verified with increased astrocytic Hsp27 from 1 to 7 days after PC. Gliosis with increased Hsp27 in the PC cortex was still present but reduced 4 weeks after PC. Therefore, PC that results in brain tolerance/neuroprotection increases neuronal Hsp70 in the PC cortex and activated astrocytic Hsp27 in the PC cortex in a temporal fashion associated with developing IT. The short duration of benign ischemia (PC) that produces IT produces a robust, long-lived cellular and protein synthetic response that extends throughout the entire cortex (i.e. well beyond the MCA perfusion territory). The resulting IT is associated with changes in astrocyte-activation that might provide increased support and protection from injury. Although both Hsp70 and Hsp27 may participate in the neuroprotection/brain tolerance induced by PC, the temporal expression patterns of these proteins indicate that they are not solely responsible for the tolerance to brain injury.

SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia.

The aim of the present study was to evaluate p38 MAPK activation following focal stroke and determine whether SB 239063, a novel second generation p38 inhibitor, would directly attenuate early neuronal injury. Following permanent middle cerebral artery occlusion (MCAO), brains were dissected into ischemic and non-ischemic cortices and Western blots were employed to measure p38 MAPK activation. Neurologic deficit and MR imaging were utilized at various time points following MCAO to monitor the development and resolution of brain injury. Following MCAO, there was an early (15 min) activation of p38 MAPK (2.3-fold) which remained elevated up to 1 h (1.8-fold) post injury compared to non-ischemic and sham operated tissue. Oral SB 239063 (5, 15, 30, 60 mg/kg) administered to each animal 1 h pre- and 6 h post MCAO provided significant (P<0.05) dose-related neuroprotection reducing infarct size by 42, 48, 29 and 14%, respectively. The most effective dose (15 mg/kg) was further evaluated in detail and SB 239063 significantly (P<0.05) reduced neurologic deficit and infarct size by at least 30% from 24 h through at least 1 week. Early (i.e. observed within 2 h) reductions in diffusion weighted imaging (DWI) intensity following treatment with SB 239063 correlated (r=0.74, P<0.01) to neuroprotection seen up to 7 days post stroke. Since increased protein levels for various pro-inflammatory cytokines cannot be detected prior to 2 h in this stroke model, the early improvements due to p38 inhibition, observed using DWI, demonstrate that p38 inhibition can be neuroprotective through direct effects on ischemic brain cells, in addition to effects on inflammation.

Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack.

Six to eight months after the Tokyo subway attack in March 1995, the neurophysiological effects of acute sarin poisoning were investigated in 18 passengers exposed to sarin (sarin cases) in the subways to ascertain the focal or functional brain deficits induced by sarin. The event-related and visual evoked potentials (P300 and VEP), brainstem auditory evoked potential, and electrocardiographic R-R interval variability (CVRR), together with the score on the posttraumatic stress disorder (PTSD) checklist, were measured in the sarin cases and the same number of control subjects matched for sex and age. None of the sarin cases had any obvious clinical abnormalities at the time of testing. The P300 and VEP (P100) latencies in the sarin cases were significantly prolonged compared with the matched controls. In the sarin cases, the CVRR was significantly related to serum cholinesterase (ChE) levels determined immediately after exposure; the PTSD score was not significantly associated with any neurophysiological data despite the high PTSD score in the sarin cases. These findings suggest that asymptomatic sequelae to sarin exposure, rather than PTSD, persist in the higher and visual nervous systems beyond the turnover period of ChE; sarin may have neurotoxic actions in addition to the inhibitory action on brain ChE.

Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.