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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRAIN AND BLOOD PRESSURE IN EXPERIMENTAL ANIMALS: Our experiments in models of experimental hypertension in the rabbit in the early 1970s demonstrated that increased activity of bulbospinal pressor neurons containing noradrenaline or serotonin mediated the elevated arterial blood pressure. Other workers had demonstrated decreased activity of noradrenergic neurons in the medulla. Accordingly, I proposed the hypothesis that the hypertension in these models arose from 'disinhibition', due to unrestrained activity of descending pressor pathways, released from the inhibitory influences present in normal animals. Over the next 15-20 years, experiments from our group and from other laboratories demonstrated that there were two distinct bulbospinal pressor pathways descending from the rostral ventral medulla, one containing adrenaline, neuropeptide Y and glutamate, and the other containing serotonin, substance P and glutamate. It has also been established that the key depressor area is in the caudal ventrolateral medulla and that the main inhibitory input, restraining the activity of the bulbospinal pressor pathways, is a short gamma-aminobutyric acid (GABA) projection ascending from the caudal ventrolateral medulla to the rostral ventral medulla. More recent experiments in the spontaneously hypertensive rat (SHR) using the immediate-early gene c-fos as a marker of neuronal activity, have demonstrated that impaired activity of this short inhibitory GABA pathway in the SHR disinhibits the bulbospinal pressor pathway, thus contributing to the hypertension in this model. BLOOD PRESSURE AND STROKE IN HUMANS: The risks of primary stroke and of secondary or recurrent stroke are both directly related to the level of blood pressure and clinical trials have clearly demonstrated that lowering blood pressure markedly reduces the incidence of primary stroke. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was launched to test the hypothesis that lowering the blood pressure in subjects who have already had a stroke or a transient ischaemic attack will also reduce the risk of stroke. A major unresolved issue for practising clinicians is how to manage the raised blood pressure that is so common in the acute phase of stroke. Accordingly, the PROGRESS investigators are planning another major multinational trial to assess the benefits and risks of lowering blood pressure in the first 3 days after the onset of a stroke.
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PMID:Volhard Lecture. Brain, blood pressure and stroke. 988 69

The aim of the study was to further investigate the effects of aniracetam, a cognition enhancer, and its metabolites on the brain cholinergic system. We measured choline acetyltransferase activity and acetylcholine release using in vivo brain microdialysis in stroke-prone spontaneously hypertensive rats (SHRSP). The enzyme activity in the pons-midbrain and hippocampus, and basal acetylcholine release in the nucleus reticularis thalami were lower in SHRSP than in age-matched Wistar Kyoto rats, indicating central cholinergic deficits in SHRSP. Repeated treatment of aniracetam (50 mg/kg p.o. x 11 for 6 days) preferentially increased the enzyme activity in the thalamus, whereas decreased it in the striatum. Among the metabolites of aniracetam, local perfusion of N-anisoyl-gamma-aminobutyric acid (GABA, 0.1 and/or 1 microM) and p-anisic acid (1 microM) into the nucleus reticularis thalami, dorsal hippocampus and prefrontal cortex of SHRSP produced a significant but delayed increase of acetylcholine release. We failed, however, to find any effect of aniracetam itself. A direct injection of N-anisoyl-GABA (1 nmol) into the pedunculopontine tegmental nucleus of SHRSP enhanced the release in the nucleus reticularis thalami. Thus, these data prove that aniracetam can facilitate central cholinergic neurotransmission via both metabolites. Based on its pharmacokinetic profile, N-anisoyl-GABA may contribute to the clinical effects of aniracetam, mainly by acting on the reticulothalamic cholinergic pathway.
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PMID:Activation of the reticulothalamic cholinergic pathway by the major metabolites of aniracetam. 1051 66

With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+ -dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors.
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PMID:Biology of ischemic cerebral cell death. 1059 20

Drugs modulating the levels of specific central neurotransmitters may influence both the rate and amount of functional recovery after focal brain injuries such as stroke. Because such drugs may be effective long after brain injury, the "therapeutic window" may be widened beyond the first few hour after stroke and an entirely new avenue for pharmacological intervention may be possible. The impact of drugs affecting norepinephrine and gamma-aminobutyric acid have been among the most extensively studied in the laboratory, and preliminary clinical data suggest similar effects in humans.
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PMID:Effects of amphetamines and small related molecules on recovery after stroke in animals and man. 1069 50

Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in the marmoset, a New World species of monkey, produces unilateral functional deficits, including motor neglect with the contralesional arm and contralesional spatial hemineglect. In this study we examined whether clomethiazole, a drug which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of the hemineglect and other deficits in this primate model of stroke. Nine monkeys received pMCAO; 1 h later four of the nine were administered clomethiazole by intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps, which released clomethiazole for 48 h. The monkeys had been trained and tested on a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks later. Three weeks after pMCAO, monkeys treated with clomethiazole had a significantly reduced degree of spatial neglect compared to untreated controls. Clomethiazole was not effective against the severe contralesional motor impairment in the current study, although it ameliorated a somewhat less severe motor deficit in a previous study in which the more distal, M2 segment of the middle cerebral artery had been occluded. Postmortem analysis of the brains showed that clomethiazole treatment had significantly reduced the area of damage in part of the parietal cortex. These data suggest that clomethiazole may reduce the neglect that can be a debilitating consequence of right-sided stroke in man.
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PMID:Clomethiazole protects against hemineglect in a primate model of stroke. 1077 98

In this review, we present evidence for the role of gamma-aminobutyric acid (GABA) neurotransmission in cerebral ischemia-induced neuronal death. While glutamate neurotransmission has received widespread attention in this area of study, relatively few investigators have focused on the ischemia-induced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GABAergic synapse. Both in vitro and in vivo models of ischemia have been used to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have been shown to alter GABA neurotransmission include changes in the Cl(-) gradient, reduction in ATP, increase in intracellular Ca(2+), generation of reactive oxygen species, and accumulation of arachidonic acid and eicosanoids. Neuroprotective strategies to increase GABA neurotransmission target both sides of the synapse as well, by preventing GABA reuptake and metabolism and increasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebral ischemia, with sedation as the only unwanted side-effect. Based on promising animal data, clinical trials with GABAergic drugs are in progress for specific types of stroke. This review attempts to provide an understanding of the mechanisms by which GABA neurotransmission is sensitive to cerebral ischemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.
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PMID:gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia. 1129 98

Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl-gamma-aminobutyric acid [corrected] (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.
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PMID:Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP. 1159 8

Adult crayfish have a neurogenic heart which is modulated via inputs from the central nervous system and neurohormones, which act on the cardiac ganglion or directly on the myocardium. This study investigates the ontogeny of cardiac regulation by exploring the temporal sequence of cardiac sensitivity to injections of cardioactive neurohormones (proctolin, serotonin and octopamine) and the neurotransmitter gamma-aminobutyric acid. The cardiac response (delta in heart rate, stroke volume, or in cardiac output) to each neurohormone at each developmental stage was assessed. The observed response elicited by each cardioactive drug was stage dependent and changed as the animals progressed from embryonic through larval and juvenile periods. During early developmental stages, octopamine, serotonin, and proctolin (10(-9)-10(-3) M) did not result in a modulation of stroke volume, yet in later developmental stages they caused significant increases in stroke volume, at comparable concentrations. Early developmental stages are capable of regulating cardiac function, however, the mechanisms appear to be quite different from those used by adults. Evidence is also provided to support the hypothesis that cardiac function is initiated prior to the establishment of an adult-like regulatory system.
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PMID:Ontogeny of neurohormonal regulation of the cardiovascular system in the crayfish Procambarus clarkii. 1168 16

The effects of aniracetam, a cognition enhancer, on extracellular levels of glutamate (Glu), gamma-aminobutyric acid (GABA) and nitric oxide metabolites (NOx) were examined in the prefrontal cortex (PFC) and the basolateral amygdala (AMG) in stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal release of Glu, was lower in the AMG of SHRSP than in normotensive Wistar Kyoto rats, whereas no difference in GABA and NOx was noted. Aniracetam (100 mg/kg, p.o.) significantly increased the area under the curve of Glu levels in the PFC, but not in the AMG, of SHRSP. Aniracetam failed to exert any remarkable effects on GABA or NOx levels in either brain region. Our findings suggest that aniracetam enhances cortical glutamatergic release, which may be the mechanism involved in the ameliorating effects of aniracetam on various neuronal dysfunctions.
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PMID:Aniracetam enhances glutamatergic transmission in the prefrontal cortex of stroke-prone spontaneously hypertensive rats. 1185 74

Neuropathic pain, whether of peripheral or central origin, is characterized by a neuronal hyperexcitability in damaged areas of the nervous system. In peripheral neuropathic pain, damaged nerve endings exhibit abnormal spontaneous and increased evoked activity, partly due to an increased and novel expression of sodium channels. In central pain, although not explored in detail, the spontaneous pain and evoked allodynia are also best explained by a neuronal hyperexcitability. The peripheral hyperexcitability is due to a series of molecular changes at the level of the peripheral nociceptor, in dorsal root ganglia, in the dorsal horn of the spinal cord, and in the brain. These changes include abnormal expression of sodium channels, increased activity at glutamate receptor sites, changes in gamma-aminobutyric acid (GABA-ergic) inhibition, and an alteration of calcium influx into cells. The neuronal hyperexcitability and corresponding molecular changes in neuropathic pain have many features in common with the cellular changes in certain forms of epilepsy. This has led to the use of anticonvulsant drugs for the treatment of neuropathic pain. Carbamazepine and phenytoin were the first anticonvulsants to be used in controlled clinical trials. Studies have shown these agents to relieve painful diabetic neuropathy and paroxysmal attacks in trigeminal neuralgia. Subsequent studies have shown the anticonvulsant gabapentin to be effective in painful diabetic neuropathy, mixed neuropathies, and postherpetic neuralgia. Lamotrigine, a new anticonvulsant, is effective in trigeminal neuralgia, painful peripheral neuropathy, and post-stroke pain. Other anticonvulsants, both new and old, are currently undergoing controlled clinical testing. The most common adverse effects of anticonvulsants are sedation and cerebellar symptoms (nystagmus, tremor and incoordination). Less common side-effects include haematological changes and cardiac arrhythmia with phenytoin and carbamazepine. The introduction of a mechanism-based classification of neuropathic pain, together with new anticonvulsants with a more specific pharmacological action, may lead to more rational treatment for the individual patient with neuropathic pain.
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PMID:Anticonvulsants in neuropathic pain: rationale and clinical evidence. 1188 43


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