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PubMed1994

Presynaptic dysfunction in Drosophila csp mutants.

Cysteine string proteins are synapse-specific proteins. In Drosophila, csp deletion mutants exhibit temperature-sensitive paralysis and early death. Here, we report that neuromuscular transmission is impaired presynaptically in these csp mutant larvae. At 22 degrees C, evoked transmitter release is depressed relative to wild type and rescued controls, and high frequency stimulation of the nerve leads to sporadic failures. At 30 degrees C, stimulus-evoked responses decline gradually before failing completely. When the temperature is returned to 22 degrees C, evoked responses recover. Spontaneous release events persist at both 22 degrees C and 30 degrees C. Since nerve conduction and postsynaptic sensitivity are unaffected, these data indicate that csp mutations disrupt depolarization-secretion coupling. This disruption explains the cellular basis of the temperature-sensitive paralysis of these organisms.

Animals↗

PubMed1999

Elementary phenotypes in the neurobiological and genetic study of schizophrenia.

This review describes the strategy of using elementary phenotypes for neurobiological and genetic linkage studies of schizophrenia. The review concentrates on practical aspects of selecting the phenotype and then understanding the confounds in its measurement and interpretation. Examples from the authors' studies of deficits in P50 inhibition and smooth pursuit eye movement dysfunction are presented. These two phenotypes share considerable similarity in their neurobiology, including a similar response to nicotine. They also appear to co-segregate with the genetic risk for schizophrenia as autosomal co-dominant phenotypes. Although most schizophrenic patients inherit these abnormalities unilinealy, i.e., from one parent, apparent bilineal inheritance produces a more severe illness, observed clinically as childhood-onset schizophrenia. The initial study showing linkage of the P50 deficit to the chromosome 15q14 locus of the alpha 7-nicotinic acetylcholine receptor is an example of the potential usefulness of these phenotypes for combined genetic and neurobiological study of schizophrenia.

Attention↗

PubMed1998

Regional alterations in neuronal activity in dystonic hamster brain determined by quantitative cytochrome oxidase histochemistry.

The neural mechanisms underlying idiopathic dystonia are currently unknown. Genetic animal models, such as the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, may be helpful to providing insights into the pathophysiology of this common movement disorder. Recent metabolic mapping studies in the hamster model, using 2-deoxyglucose autoradiography, demonstrated altered 2-deoxyglucose uptake in motor areas such as the striatum, ventral thalamic nuclei, red nucleus, and deep cerebellar nuclei, during dystonic attacks. Whereas the 2-deoxyglucose method is thought to reflect mainly acute alterations of synaptic activity, determination of cytochrome oxidase activity has been suggested as a method of choice to examine sustained baseline changes in neuronal activity. Therefore, in the present study quantitative cytochrome oxidase histochemistry was used to identify chronic regional alterations in the absence of dystonic attacks in mutant hamsters. For comparison with recent 2-deoxyglucose studies, cytochrome oxidase activity was also determined during a dystonic attack, which was induced by mild stress. Cytochrome oxidase was determined in 109 brain regions of dystonic hamsters and non-dystonic, age-matched control hamsters. In the absence of a dystonic attack, a tendency to decreased cytochrome oxidase activity was found in most brain regions, possibly due to retarded brain development in mutant hamsters. Significant decreases in cytochrome oxidase activity were found in motor areas and limbic structures, such as hippocampus, piriform cortex, fundus striatum, globus pallidus, substantia nigra pars reticulata, mediodorsal nucleus of the thalamus, ventral pallidum, and interpositus nucleus of the cerebellum. After induction of a dystonic attack, the trend of decreased cytochrome oxidase activity disappeared, except in globus pallidus and interpositus nucleus of the cerebellum. Although the significant alterations in cytochrome oxidase activity in the absence of a dystonic attack were moderate, the data are in line with previous findings in the mutant hamsters, indicating that dysfunctions of the basal ganglia and their output nuclei are involved in the dystonic condition. Altered neural activity in limbic structures, found in the absence of dystonic attacks in mutant hamsters, may contribute to the stress-susceptibility of the animals.

Animals↗

PubMed2001

Glucose feeding exacerbates parathion-induced neurotoxicity.

Excessive dietary intake of sugars could alter various biotransformation processes and the pharmacological and toxicological properties of numerous xenobiotics. In the present study, the effects of glucose supplementation were examined on the neurotoxicity of the organophosphorus (OP) pesticide parathion (PS) and its active metabolite, paraoxon (PO), a potent inhibitor of acetylcholinesterase (AChE). Rats (n = 6-12/treatment group) were given free access to tap water or 15% glucose (w/v) in tap water beginning 7 d prior to OP toxicant exposure. Food, caloric intake, and body weight were measured daily. Animals were challenged with either PS (4.5, 9, or 18 mg/kg, sc) or PO (0.3 0.5, or 0.7 mg/kg, sc) and clinical signs of neurotoxicity (i.e., autonomic dysfunction, involuntary movements) were recorded daily for the following 13 d. Glucose feeding was associated with a dramatic drop (approximately 50%) in feed intake and an increase (approximately 20% in total caloric consumption over the 7 d prior to OP exposure. Functional toxicity associated with PS exposure was increased in glucose-fed (GF) rats, but the glucose diet had no apparent effect on clinical signs of toxicity following PO treatment. Glucose feeding increased the magnitude of AChE inhibition in the frontal cortex and plasma at lower dosages (i.e., 4.5 and 9 mg/kg) 3 d following PS treatment. Time-course studies (3, 7, and 11 d after PS exposure, 18 mg/kg, sc) indicated significantly greater brain and plasma AChE inhibition in glucose-fed animals at later time points. In contrast, glucose feeding had no effect on the degree of AChE inhibition following PO exposure. Neither liver microsomal oxidative desulfuration of PS, nor liver or plasma paraoxonase, nor liver or plasma carboxylesterase activities were measurably affected by glucose feeding. Downregulation of muscarinic receptors 7 d after PS exposure (18 mg/kg, sc) was more extensive in GF rats. It is postulated that excessiveglucose consumption decreases the intake of other dietary components, in particular amino acids, limiting the de novo synthesis of AChE and consequent recovery of synaptic transmission. Due to the shorter duration of inhibition following PO exposure, sponta neous reactivation of AChE may be more important than de novo protein synthesis in recovery of function, and thus with the effects of glucose feeding on its toxicity. Individuals that derive a large proportion of their calories from sugars may be at higher risk of acute toxicity from organophosphorus pesticides such as PS.

Animals↗

PubMed1995

Upper motor neuron dysfunction reduces the EMG evidence of myasthenia gravis.

Hyposensitivity to the action of nondepolarizing muscle relaxants has been frequently observed in patients with upper motor neuron dysfunction and in patients treated with antiepileptic drugs. To ascertain whether the same conditions are also characterized by a reduced sensitivity to the effects of anti-acetylcholine-receptor antibodies occurring in myasthenia gravis, bilateral investigations of neuromuscular transmission were conducted on proximal and distal muscles of a myasthenic patients with a long history of hemiparesis and epilepsy. It was observed that electromyographic evidence of myasthenia gravis was absent in distal muscles (and low in proximal ones of the paretic side. Even though the influence of antiepileptic treatment could not be assessed with certainty in this patient, indirect evidence suggests that hyposensitivity to anti-acetylcholine-receptor antibodies is an unlikely consequence of neuromuscular changes induced by anticonvulsants.

Adult↗

PubMed1997

A risk-benefit assessment of mirtazapine in the treatment of depression.

Mirtazapine is the first of a new class of antidepressants, the noradrenergic and specific serotonergic antidepressants (NaSSA). Its antidepressant effect appears to be related to its dual enhancement of central noradrenergic and serotonin 5-HT1 receptor-mediated serotonergic neurotransmission. Mirtazapine possesses a number of useful pharmacokinetic characteristics such as good absorption, linear pharmacokinetics over the recommended dosage range (15 to 80 mg/day), and an elimination half-life of 20 to 40 hours, thereby allowing once-daily administration. However, since the drug is extensively metabolised by the hepatic cytochrome P450 (CYP) system and is excreted mainly in the urine, its clearance may be reduced by hepatic or renal impairment. In vitro data suggest that from a clinical point of view it is unlikely that mirtazapine would inhibit the metabolism of coadministered drugs metabolised by CYP1A2, CYP2D6 or CYP3A4. In vivo data from a study in extensive and poor metabolisers of debrisoquine indicate that strong inhibitors of CYP2D6 would have no effect on the concentration of racemic mirtazapine. In some placebo-controlled studies mirtazapine showed an early onset of antidepressant action, with significant reductions in total Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale scores (relative to placebo) noted as early as 1 week after starting treatment. This therapeutic advantage was subsequently maintained during treatment, with mirtazapine proving significantly superior to placebo at treatment end-point in the majority of studies. In comparative trials, the antidepressant efficacy of mirtazapine was comparable with that of tricyclic antidepressants such as amitriptyline, clomipramine and doxepin, and in 2 studies superior to that of trazodone and fluoxetine. Mirtazapine appears to have a broad spectrum of activity, reflected in its efficacy in a variety of clinical settings. Its additional beneficial effects on the symptoms of anxiety and sleep disturbance associated with depression may reduce the need for concomitant anxiolytic and hypnotic medication seen with some antidepressants. Mirtazapine has demonstrated superior tolerability to the tricyclic antidepressants and trazodone, primarily on account of its relative absence of anticholinergic, adrenergic and serotonin-related adverse effects, in particular gastrointestinal adverse effects and sexual dysfunction. It appears that increased sedation associated with the drug is related to subtherapeutic dosages, and that it is reported in substantially fewer patients when the drug is used in appropriate dosages (> or = 15 mg as a single evening dose) from the beginning of treatment. Although 2 cases of reversible severe symptomatic neutropenia have been reported in clinical trials, there have been no additional reports of symptomatic neutropenia since the introduction of this drug to various countries in September 1994. Currently available data and initial clinical experience suggest that with its combination of dual action, simple pharmacokinetics, and clinical efficacy and tolerability, mirtazapine appears to be an important advance in the pharmacotherapy of depression.

Adult↗

PubMed2001

Spatiotemporal dynamics of brain-derived neurotrophic factor mRNA induction in the vestibulo-olivary network during vestibular compensation.

Vestibular compensation, which is the behavioral recovery from vestibular dysfunction produced by unilateral labyrinthectomy (UL), is attributed to functional and structural reorganization of neural networks in the central vestibular system. To assess the possible contribution of brain-derived neurotrophic factor (BDNF) to this recovery process, we investigated changes in mRNA expression levels in the central vestibular system after UL. We evaluated BDNF mRNA expression levels by quantitative reverse transcription-PCR and in situ hybridization. We found that BDNF mRNA is differentially induced in the medial vestibular nucleus ipsilateral to UL and in the prepositus hypoglossi and inferior olive on the contralateral side. The BDNF mRNA induction lasted for at least 24 hr and returned to the basal expression level within 72 hr after UL. In contrast to BDNF mRNA induction, the expression of an immediate-early gene, c-fos, quickly reached the maximum level at 3 hr and decreased to the basal level within 24 hr after UL. Neither BDNF or c-fos induction was observed in sham-operated animals. The persistent induction of BDNF after UL temporally corresponded to early behavioral manifestations of vestibular compensation. We further found that trkB mRNA was expressed in the central vestibular network at high levels, although its expression levels did not change over time after UL. Because BDNF is implicated in regulating synaptic structure and function, these results provide support for the hypothesis that BDNF is involved in neuronal reorganization that allows vestibular compensation.

Adaptation, Physiological↗

PubMed1994

Effect of selenium on lead-induced neurotoxicity in different brain regions of adult rats.

The different effects of lead exposure in young children and adults, and inconsistencies between in vivo and in vitro studies as well as between experimental and clinical data suggest that lead toxicity may have different mechanisms. During the developmental phase, lead neurotoxicity results in permanent dysfunction, but its neuropharmacological toxicity as seen in adults might involve its interaction with micronutrients such as calcium and zinc. Lead administered orally in a dose of 20 mg/kg for 8 weeks was found to inhibit the enzyme activity of succinic dehydrogenase, acetylcholine esterase and Na+/K+ ATPase both in the cerebrum and in the cerebellum. Selenium also affected these enzymes when administered in a dose of 0.5 ppm for 8 weeks. When lead and selenium were administered simultaneously the inhibition of the three enzyme activities was considerably alleviated. However, when selenium (0.5 ppm) was given only for 15 days after exposure to lead, the activity of the enzymes was much reduced when compared with control.

Analysis of Variance↗

PubMed2004

Posttranslational modifications of tau--role in human tauopathies and modeling in transgenic animals.

Alzheimer's disease (AD) is characterized histopathologically by beta-amyloid-containing plaques, neurofibrillary tangles (NFT), reduced synaptic density, and neuronal loss in selected brain areas. Plaques consist of aggregates of a small peptide termed Abeta which is derived by proteolysis of the larger amyloid precursor protein APP, whereas NFT are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Tau pathology in the presence of scant or no beta-amyloid plaques characterizes additional neurodegenerative disorders collectively called tauopathies. In the course of plaque and NFT formation, the major proteinaceous components of these lesions undergo post-translational modifications. In the case of tau, these include phosphorylation of mainly serine and threonine, but also tyrosine residues. In addition, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products (AGEs). This review aims to provide insight into the complexity of tau modifications in human tauopathies such as AD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Selected aspects of the post-translational modification of tau have been reproduced in transgenic animal models. Most of this work has been done in mice, but insight has also been gained from studies in the sea lamprey, the nematode C. elegans and Drosophila. Attempts have been made to link specific post-translational modifications with tau aggregation and nerve cell dysfunction.

Animals↗

PubMed1995

Developmental changes in newborn lamb brain mitochondrial activity and postasphyxial lipid peroxidation.

Previously, our laboratory has demonstrated inhibition of mitochondrial state 3 (ADP-dependent) respiration 5 min after resuscitation from an asphyxial insult in lambs less than 3 days of age. Older lambs were resistant to this transient mitochondrial dysfunction. This study was designed to examine if age-related differences in baseline state 3 mitochondrial respiration, electron transport chain activity, or susceptibility to oxygen free radical-mediated lipid peroxidation were related to the previously observed differences in postasphyxial mitochondrial respiration. Mitochondrial respiration was measured in 24 nonasphyxiated control lambs aged 1-10 days using four different substrates. Electron transport chain activity was assessed in 15 of these lambs, and lipid peroxidation measured as conjugated diene production was measured in 11 of these lambs. These lambs were all ventilated to maintain normal blood gases for a time period equal to the length of the hypoxic insult in asphyxiated lambs (see below), after which samples of brain were removed for isolation of mitochondria. A second group of 11 lambs (seven < or = 3 days of age and four > 3 days of age) were asphyxiated. The insult was a 75-to-90-min episode of hypoxia and hypercarbia that resulted in bradycardia and systemic hypotension over the final 15 min of the insult. At the end of asphyxia, the lambs were resuscitated and returned to control ventilator settings. Samples of brain were removed 5 min after resuscitation. Postasphyxia electron transport chain activity and lipid peroxidation were measured. All measurements described above were done in both nonsynaptic (primarily glial in origin) and synaptic mitochondria. State 3 mitochondrial respiration varied significantly with age, decreasing by an average of 41.2% +/- 11.1% (mean +/- SEM) from Day 2 to Day 5-6 and then increasing back to levels similar to Day 2 by Day 8-10 in nonsynaptic mitochondria. State 3 respiration in synaptic mitochondria decreased 60.6% +/- 5.2% from Day 2 to Day 5-6 before returning to levels similar to Day 2 by Day 8-10. Resting (nonADP-dependent) state 4 respiration demonstrated similar developmental patterns. Electron transport chain activities did not vary with age in the nonasphyxiated control animals. In addition, an asphyxial insult did not diminish electron transport chain activities in either lambs < or = 3 days old or those > 3 days of age.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine Nucleotides↗

PubMed2005

Fast cerebellar oscillation associated with ataxia in a mouse model of Angelman syndrome.

Ataxia may result from various cerebellar cortex dysfunctions. It is included in the diagnostic criteria of Angelman syndrome, a human neurogenetic condition. In order to better understand the cerebellar dysfunction in this condition, we recorded in vivo cerebellar activity in a mouse model of Angelman syndrome produced by null mutation of the maternal Ube3a gene. We found fast oscillation (approximately 160 Hz) in the cerebellar cortex sustained by abnormally increased Purkinje cell firing rate and rhythmicity. This oscillation is inhibited by sensory stimulation and gap junction or GABA(A) receptor blockers. A physiologically similar oscillation was previously found in mice lacking calcium-binding proteins that also present ataxia, but never in wild-type mice. We propose that fast oscillation in the cerebellar cortex is implicated in the cerebellar symptomatology of Angelman syndrome.

Angelman Syndrome↗

PubMed1999

Role of mitochondrial dysfunction in the Ca2+-induced decline of transmitter release at K+-depolarized motor neuron terminals.

The present study tested whether a Ca2+-induced disruption of mitochondrial function was responsible for the decline in miniature endplate current (MEPC) frequency that occurs with nerve-muscle preparations maintained in a 35 mM potassium propionate (35 mM KP) solution containing elevated calcium. When the 35 mM KP contained control Ca2+ (1 mM), the MEPC frequency increased and remained elevated for many hours, and the mitochondria within twitch motor neuron terminals were similar in appearance to those in unstimulated terminals. All nerve terminals accumulated FM1-43 when the dye was present for the final 6 min of a 300-min exposure to 35 mM KP with control Ca2+. In contrast, when Ca2+ was increased to 3.6 mM in the 35 mM KP solution, the MEPC frequency initially reached frequencies >350 s-1 but then gradually fell approaching frequencies <50 s-1. A progressive swelling and eventual distortion of mitochondria within the twitch motor neuron terminals occurred during prolonged exposure to 35 mM KP with elevated Ca2+. After approximately 300 min in 35 mM KP with elevated Ca2+, only 58% of the twitch terminals accumulated FM1-43. The decline in MEPC frequency in 35 mM KP with elevated Ca2+ was less when 15 mM glucose was present or when preparations were pretreated with 10 microM oligomycin and then bathed in the 35 mM KP with glucose. When glucose was present, with or without oligomycin pretreatment, a greater percentage of twitch terminals accumulated FM1-43. However, the mitochondria in these preparations were still greatly swollen and distorted. We propose that prolonged depolarization of twitch motor neuron terminals by 35 mM KP with elevated Ca2+ produced a Ca2+-induced decrease in mitochondrial ATP production. Under these conditions, the cytosolic ATP/ADP ratio was decreased thereby compromising both transmitter release and refilling of recycled synaptic vesicles. The addition of glucose stimulated glycolysis which contributed to the maintenance of required ATP levels.

Animals↗

PubMed2006

Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations.

Impairments in certain cognitive functions mediated by the dorsolateral prefrontal cortex, such as working memory, are core features of schizophrenia. Convergent findings suggest that these disturbances are associated with alterations in markers of inhibitory gamma-aminobutyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. Specifically, reduced gamma-aminobutyric acid synthesis is present in the subpopulation of gamma-aminobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyramidal neurons contributes to a reduction in the synchronized neuronal activity that is required for working memory function. Several lines of evidence suggest that these changes may be either secondary to or exacerbated by impaired signaling via the N-methyl-d-aspartate class of glutamate receptors. These findings suggest specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.

Animals↗

PubMed1999

Serotonin hypothesis of winter depression: behavioral and neuroendocrine effects of the 5-HT(1A) receptor partial agonist ipsapirone in patients with seasonal affective disorder and healthy control subjects.

Winter depressions in seasonal affective disorder (SAD) are associated with central serotonergic (5-HT) dysfunction. SAD patients demonstrate rather specific, state-dependent, abnormal increases in 'activation-euphoria' ratings following intravenous infusion of the 5-HT receptor agonist meta-chlorophenylpiperazine (m-CPP). Several studies are also consistent with abnormal serotonergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis in SAD. Here, we investigated the effects of the 5-HT1A receptor partial agonist ipsapirone, which produces behavioral effects and HPA-axis activation, to further characterize the 5-HT receptor subtype-specificity of these disturbances in SAD. Eighteen SAD patients and 18 control subjects completed two drug challenges (ipsapirone 0.3 mg/kg and placebo) separated by 3-5 days in randomized order. We measured behavioral responses with the NIMH self-rating scale, and plasma ACTH, cortisol, and prolactin concentrations. Compared with placebo, ipsapirone was associated with significant increases in self-rated 'functional deficit' and 'altered self-reality', and in each of the hormones. There were no differences between groups on any measures. The level of depression in SAD patients was inversely correlated with their ipsapirone-induced cortisol responses. There were significant drug x order effects on baseline 'anxiety' scores, ACTH and cortisol concentrations, such that subjects were significantly more stressed (higher 'anxiety', ACTH and cortisol) prior to their first challenge compared with their second. In conclusion, post-synaptic 5-HT1A receptors appear to function normally in SAD. The previously observed m-CPP-induced behavioral abnormality may be mediated by either 5-HT2C or 5-HT7 receptors.

Adrenocorticotropic Hormone↗

PubMed2006

Impaired motor function in mice with cell-specific knockout of sodium channel Scn8a (NaV1.6) in cerebellar purkinje neurons and granule cells.

The Scn8a gene encodes the voltage-gated Na channel alpha subunit Na(V)1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate Scn8a in all cells result in severe motor dysfunction and premature death, precluding analysis of the physiological role of Na(V)1.6 in different neuronal types. To test the effect of cerebellar Na(V)1.6 on motor coordination in mice, we used the Cre-lox system to eliminate Scn8a expression exclusively in Purkinje neurons (Purkinje KO) and/or granule neurons (granule KO). Whereas granule KO mice had only minor behavioral defects, adult Purkinje KO mice exhibited ataxia, tremor, and impaired coordination. These disorders were exacerbated in double mutants lacking Scn8a in both Purkinje and granule cells (double KO). In Purkinje cells isolated from adult Purkinje KO and double KO but not granule KO mice, the ratio of resurgent-to-transient tetrodotoxin- (TTX)-sensitive Na current amplitudes decreased from approximately 15 to approximately 5%. In cerebellar slices, Purkinje cell spontaneous and maximal firing rates were reduced 10-fold and twofold relative to control in Purkinje KO and double KO but not granule KO mice. Additionally, short-term plasticity of high-frequency parallel fiber EPSCs was altered relative to control in Purkinje KO and double KO but not granule KO mice. These data suggest that the specialized kinetics of Purkinje Na channels depend directly on Scn8a expression. The loss of these channels leads to a decrease in Purkinje cell firing rates as well as a modification of the synaptic properties of afferent parallel fibers, with the ultimate consequence of disrupting motor behavior.

Action Potentials↗

PubMed2006

Inhibition of calpain and caspase-3 prevented apoptosis and preserved electrophysiological properties of voltage-gated and ligand-gated ion channels in rat primary cortical neurons exposed to glutamate.

Glutamate toxicity in traumatic brain injury, ischemia, and Huntington's disease causes cortical neuron death and dysfunction. We tested the efficacy of calpain and caspase-3 inhibitors alone and in combination to prevent neuronal death and preserve electrophysiological functions in rat primary cortical neurons following glutamate exposure. Cortical neurons exposed to 0.5 microM glutamate for 24 h committed mostly apoptotic death as determined by Wright staining and ApopTag assay. Levels of expression, formation of active forms, and activities of calpain and caspase-3 were increased following glutamate exposure. Also, in situ double labeling identified conformationally active caspase-3-p20 fragment and chromatin condensation in apoptotic neurons. Pretreatment of cortical neurons with 0.2 microM N-benzyloxylcarbonyl-Leu-Nle-aldehyde (calpain-specific inhibitor) and 100 microM N-benzyloxylcarbonyl-Asp(OCH3)-Glu(OCH3)-Val-Asp(OCH3)-fluoromethyl ketone (caspase-3-specific inhibitor) provided strong neuroprotection. Standard patch-clamp techniques were used to measure the whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptors, and kainate receptors. The lack of a change in capacitance indicated that neurons treated with inhibitor(s) plus glutamate did not undergo apoptotic shrinkage and maintained the same size as the control neurons. Whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptors, and kainate receptors were similar in amplitude and activation/inactivation kinetics for cells untreated and treated with inhibitor(s) and glutamate. Spontaneous synaptic activity as observed by miniature end-plate currents was also similar. Prevention of glutamate-induced apoptosis by calpain and caspase-3 inhibitors preserved normal activities of crucial ion channels such as Na+ channels, N-methyl-D-aspartate receptors, and kainate receptors in neurons. Our studies strongly imply that calpain and caspase-3 inhibitors may also provide functional neuroprotection in the animal models of traumatic brain injury and neurodegenerative diseases.

Amino Acid Chloromethyl Ketones↗

PubMed2004

Postoperative residual curarisation: complication or malpractice?

Neuromuscular blocking drugs are often used in anaesthesia; in some types of surgery, their continuous infusion is indicated to limit the otherwise high incidence of movement. A large amount of postoperative residual curarisation is found after a single bolus, but more especially when continuous infusions are used in healthy patients and even more so in those with organ dysfunction or undergoing special types of surgery. Therefore, one should always optimise the dose requirements over time using neuromuscular transmission monitoring. Such monitoring should also help the clinician to antagonise selectively the neuromuscular block at the end of surgery. One should probably avoid routine antagonisation, especially in certain subgroups of patients, until a selective and safe reversal agent has been developed. At present, then, the only objective and reliable guide to facilitating the decision for selective antagonisation is the neuromuscular transmission monitor. Recent data and editorials warning about postoperative residual curarisation after boluses and infusions of neuromuscular blocking drugs have made residual curarisation one of the most feared complications in anaesthesia. There may be a consequent issue of malpractice if neuromuscular transmission monitoring is not used and/or pharmacological antagonisation is not performed.

Anesthesia Recovery Period↗

PubMedDate not supplied

Graft-induced recovery of cognitive function after diffuse and focal brain damage: implications for neural transplantation in man.

Two types of cognitive impairment in the rat are compared: deficits arising after damage to the forebrain cholinergic projection system perikarya induced by chronic alcohol treatment or excitotoxic lesions as a model for cholinergic dysfunction in neurodegenerative disease; and impairment after intrahippocampal ischaemic CA1 cell loss induced by occlusion of vertebral and carotid arteries (four vessel occlusion: 4 VO), resembling the cerebral consequences of heart attack in man. Findings to date indicate that cholinergic depletion disrupts performance on a broad range of tasks, suggesting a deficit in attention, whereas ischaemic damage induces a relatively specific impairment in spatial learning and precise localisation. Functional recovery from both types of brain damage has been observed following neural transplantation, but the mechanisms of action appear to differ. In animals with cholinergic damage, donor tissue from a variety of sources promoted functional recovery, including cholinergic-rich homografts from two different regions of the foetal brain (basal forebrain and pontomesencephalon), grafts of primary cells enriched with glia, and cultured neuroblastoma cells, provided that the grafts are placed in the terminal areas of cholinergic projections (cortex and/or hippocampus) and not in the damaged cell body regions (basal forebrain or medial septal area). In contrast, in animals with CA1 cell loss, only homotypic grafts dissected from the foetal CA1 field, and not from the CA3 or dentate gyrus fields, promoted functional recovery, when placed in the alveus, close to the damaged host CA1 area. These findings suggest that whereas grafts in cholinergic depleted animals may exert their functional effects through non-specific synaptic links with host neurons and/or release of trophic factors, CA1 field grafts may serve to bridge or repair the damaged host hippocampal circuit.

Animals↗