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Biomedical subjects

Michael V Johnston

Publications and source records attributed to Michael V Johnston.

9 recordsLinked to original sources
PubMed2003

Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress.

BACKGROUND AND PURPOSE: Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels are present in the brain, and several reports have shown that mitoK(ATP) channel openers protect the brain against ischemic injury. However, the precise mechanisms of this protection are not well established. We hypothesized that mitoK(ATP) channel openers prevent apoptosis by preserving mitochondrial membrane potential. METHODS: We investigated the effect of mitoK(ATP) channel openers on apoptosis induced by oxidative stress using cultured cerebellar granule neurons. RESULTS: The mitoK(ATP) channel opener diazoxide (100 micromol/L) significantly suppressed the number of cells with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive nuclei and the increase in caspase-3 activity induced by 20 micromol/L H2O2. Diazoxide and another opener, pinacidil, prevented the loss of mitochondrial inner membrane potential (Delta(Psi)m) induced by H2O2. These effects were abolished by 5-hydroxydecanoate (500 micromol/L), a mitoK(ATP) channel blocker. Cyclosporin A and bongkrekic acid, inhibitors of the mitochondrial permeability transition pore, also prevented Delta(Psi)m loss, confirming the involvement of the mitochondrial permeability transition in the apoptotic cascade in neurons. Furthermore, diazoxide prevented the increase in extracellular glutamate concentration induced by H2O2, but this effect was not attributable to activation of surface K(ATP) channels. CONCLUSIONS: MitoK(ATP) channel openers inhibited apoptosis by preserving mitochondrial inner membrane potential. These beneficial effects may suggest a possible new target for neuroprotection.

Adenosine Triphosphate↗
PubMed2003

Foreword.

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Child↗
PubMed2003

Brain plasticity in paediatric neurology.

Plasticity includes the brain's capacity to be shaped or moulded by experience, the capacity to learn and remember, and the ability to reorganize and recover after injury. Mechanisms for plasticity include activity-dependent refinement of neuronal connections and synaptic plasticity as a substrate for learning and memory. The molecular mechanisms for these processes utilize signalling cascades that relay messages from synaptic receptors to the nucleus and the cytoskeleton to control the structure of axons and dendrites. Several paediatric neurological disorders such as neurofibromatosis-1, Fragile X syndrome, Rett syndrome, and other syndromic and non-specific forms of mental retardation involve lesions in these signalling pathways. Acquired disorders such as hypoxic-ischaemic encephalopathy, lead poisoning and epilepsy also involve signalling pathways including excitatory glutamate receptors. Information about these 'plasticity pathways' is useful for understanding their pathophysiology and potential therapy.

Adaptation, Physiological↗
PubMed2003

Learning, memory, and transcription factors.

Cognitive disorders in children have traditionally been described in terms of clinical phenotypes or syndromes, chromosomal lesions, metabolic disorders, or neuropathology. Relatively little is known about how these disorders affect the chemical reactions involved in learning and memory. Experiments in fruit flies, snails, and mice have revealed some highly conserved pathways that are involved in learning, memory, and synaptic plasticity, which is the primary substrate for memory storage. These can be divided into short-term memory storage through local changes in synapses, and long-term storage mediated by activation of transcription to translate new proteins that modify synaptic function. This review summarizes evidence that disruptions in these pathways are involved in human cognitive disorders, including neurofibromatosis type I, Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Rett syndrome, tuberous sclerosis-2, Down syndrome, X-linked alpha-thalassemia/mental retardation, cretinism, Huntington disease, and lead poisoning.

Animals↗
PubMed2002

Pharmacological preconditioning ameliorates neurological injury in a model of spinal cord ischemia.

BACKGROUND: Pharmacological openers of mitochondrial ATP-sensitive potassium (mitoKATP) channels have been shown to mimic ischemic preconditioning (IPC) in both the brain and myocardium. We hypothesized that similar endogenous mechanisms exist in the spinal cord and that diazoxide, a potent mitoKATP opener, could reduce neurologic injury after aortic cross-clamping in a model of spinal cord ischemia. METHODS: The infra-renal aorta was cross-clamped in 45 male New Zealand white rabbits for 20 minutes. Control animals received no pretreatment. Diazoxide-treated animals were dosed (5 mg/kg) 15 minutes before cross-clamp. A third group underwent 5 minutes of IPC 30 minutes before cross-clamp. Two groups received KATP antagonists, 5-hydroxydecanoic acid (5-HD, 20 mg/kg) or glibenclamide (1.0 mg/kg), before diazoxide administration. Systemic hypotension was induced in a final group with excess isoflurane. Tarlov Scoring was used to assess neurologic function at 24 and 48 hours, after which, the spinal cords were procured for histopathological analysis. RESULTS: Tarlov scoring demonstrated marked improvement in the Diazoxide group compared with control at 24 hours (p < 0.02) and 48 hours (p < 0.009). Moreover, no further neurologic injury occurred in this group at 7 days. IPC-treated animals showed neurologic improvement but were not significantly different from controls. Further, administration of glibenclamide was effective in antagonizing diazoxide's protective effect. CONCLUSIONS: Administration of diazoxide resulted in significant improvement in neurologic outcome in this model. This protective effect improved outcome at both early and late time points. Further, the antagonistic effect of glibenclamide implicates diazoxide's ATP-dependent potassium channel agonism as the mechanism of protection. Overall, this study suggests that diazoxide may be useful in the prevention of neurologic injury after thoracic aneurysm surgery.

Animals↗
PubMed2002

Neonatal electrolytic lesions of the basal forebrain stunt plasticity in mouse barrel field cortex.

Previous studies have shown that neonatal electrolytic lesions of basal forebrain cholinergic projections in mice lead to a transient cholinergic depletion of neocortex and to permanent alterations in cortical cytoarchitecture and in cognitive performance. The present study examines whether neonatal electrolytic lesions of the basal forebrain modify neocortical plasticity. Using cytochrome oxidase histochemistry, we compared cross-sectional areas of individual barrels in the barrel field of four groups of postnatal day 8 (P8) old mice that on P1 received either (1) right electrolytic lesions of the basal forebrain, (2) left C row 1-4 whisker follicle ablations, (3) combined lesion treatments or (4) ice anesthesia only. The size of barrels in basal forebrain lesioned animals was not significantly different from controls. However, the plastic response to whisker removal was compromised in basal forebrain lesioned animals. An index of plasticity, the ratio of row D/row C areas, was reduced significantly in the combined nBM lesioned/follicle ablation group. Compared to whisker-lesioned mice, the expansion in rows B and D and the shrinkage in the lesioned row C area were diminished in the combined treatment group. The present findings correspond to those from a study of rats injected with a cholinergic immunotoxin [Cereb. Cortex 8 (1998) 63]. These results suggest that cholinergic inputs play a role in regulating plasticity as well as in the morphogenesis of mouse sensory-motor cortex.

Acetylcholine↗
PubMed2002

Brain glucose metabolism in Rett Syndrome.

Rett syndrome is a progressive neurologic disorder affecting girls in early childhood with loss of achieved psychomotor abilities and mental retardation. Six sedated female patients (4 to 15 years of age) with a diagnosis of Rett syndrome were studied with [(18)F]fluorodeoxyglucose (FDG) and underwent positron emission tomography scanning of the brain. Relative tracer concentrations between different areas of the brain were assessed, and results were compared with 18 age-matched control subjects. Patients were divided into two age groups: 3 to 8 years of age and 9 to 15 years of age. A relative decrease in [(18)F]FDG uptake in the lateral occipital areas in relation with the whole brain and a relative increase in the cerebellum was evident in both age groups (P < 0.001, unpaired Student t test). A relative increase in frontal tracer uptake was observed in the younger group. Sensorimotor areas and relations between cortical and subcortical structures were preserved in all patients. Changes in glucose cerebral metabolism resemble the regional distribution of normal children less than 1 year of age, likely reflecting a maturational arrest. Changes in frontal areas parallel those in postmortem N-methyl-D-aspartate receptor densities and could correlate with different clinical stages of the disease. This pattern differs from those described in Down syndrome, autism, and Alzheimer's disease.

Adolescent↗
PubMed2002

Mechanisms of hypoxic neurodegeneration in the developing brain.

Asphyxia and other insults to the developing brain are responsible for several human neurodevelopmental disorders. The pattern of neonatal brain injury differs from that seen in the adult nervous system, and there are wide differences in regional vulnerability. Recent evidence suggests that two events that contribute to this pattern of selective vulnerability are developmental changes in excitatory glutamate-containing neurotransmitter circuits and the propensity for immature neurons to die by apoptosis rather than necrosis. Developmental up-regulation of NMDA receptors with enhanced function and increased expression of caspase-3 at critical periods in development are linked to these mechanisms. Although these molecular changes enhance the developing brain's capacity for plasticity by helping to prune redundant synapses and neurons, they can become "Achilles heels" in the face of a brain energy crisis.

Apoptosis↗