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

Motor cortex stimulation (MCS) was proposed by Tsubokawa in 1991 for the treatment of post-stroke thalamic pain. Since that time, the indications have been increased and included trigeminal neuropathic pain and later other types of central and peripheral deafferentation pain. The results reported in the literature are quite good; the mean long-term success rate is 80% in facial pain and 53% in non-facial pain. Our own results are less impressive: 4 of 14 patients (28%) experienced a greater than 40% pain relief, but in 2 of them the effect faded with time. Only few minor complications have been reported. The accurate placement of the epidural electrode over the motor cortex that somatotopically corresponds to the painful area is believed to be essential for pain relief. Predictive factors included the response to pharmacological tests, the relative sparing from the disease process of the cortico-spinal tract and the sensory system, and the analgesic response achieved during the test period of MCS. A possible predictive factor might be a test of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. MCS may act by rebalancing the control of non-nociceptive sensory inputs over nociceptive afferents at cortical, thalamic, brainstem and spinal level. In addition, it may interfere with the emotional component of nociceptive perception. Biochemical processes involving endorphins and GABA may also be implicated in the mechanism of MCS. It is time for a large multicenter prospective randomized double blind study evaluating not only the effect of MCS on pain (based on the available guidelines for assessment of neuropathic pain), but also the optimal electrode placement and stimulation parameters, and the possible relationship with the response to rTMS. New electrode design and a new generation of stimulators may help in improving the results.
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PMID:Motor cortex stimulation for chronic non-malignant pain: current state and future prospects. 1769 Dec 88

During cerebral ischemia, there is excessive activity of excitatory amino acids, especially glutamate. Activation of glutamate receptors leads to a marked increase in intracellular calcium, which in turn leads to activation of intracellular enzymes and neuronal death--the so-called excitotoxic cascade. The calcium antagonist nimodipine, which acts at L-type calcium channels, was tested for a putative neuroprotectant effect in patients with acute ischemic stroke, but no beneficial effect was demonstrated. Glutamate receptors are attractive targets for neuroprotectant drugs because glutamate plays a central role in the excitotoxic cascade. Clinical trials of NMDA (N-methyl-D-aspartate) antagonists have been disappointing, however, and psychiatric side effects seem to be a general problem with this class of drug. Another strategy proposed for interfering with NMDA receptor function is the infusion of magnesium. The NMDA receptor is normally blocked by magnesium ions and will only respond to glutamate when this magnesium-induced block is removed on depolarization. A large clinical trial to investigate possible neuroprotection by magnesium is underway. The NMDA receptor also has a glycine-binding site and a polyamine-binding site, and the cation channel will only open in response to glutamate if glycine and polyamines are already bound to these obligatory modulatory sites. Gavestinel is selective for the glycine-binding site, and eliprodil for the polyamine site, but large international clinical trials have failed to find any beneficial effects in patients with acute ischemic stroke. Neurotoxic free radicals are also generated during cerebral ischemia. Laboratory stroke models suggest that free radical scavengers might be effective neuroprotectants. One of these, NXY-059, was effective in several animal studies, and preliminary studies in human subjects show that plasma concentrations that are neuroprotective in animal models can be achieved and are well tolerated. Lubeluzole interferes with the glutamate-induced neuronal damage mediated through the formation of nitric oxide. However, a meta-analysis of all clinical trials of lubeluzole was unable to detect a neuroprotectant effect of the drug. There is now some evidence that, in addition to necrosis, some neurons die as a result of apoptosis after cerebral ischemia. Several drugs that interfere with the apoptosis cascade, for example, caspase inhibitors, are under investigation. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) is also undergoing a second large clinical trial in patients with major ischemic strokes. This drug's mechanism of action is not completely clear, but it is known to activate a nonbenzodiazepine site on the GABA(A) (gamma-aminobutyric acid) receptor. This causes increased chloride conductance and hyperpolarization. In vitro clomethiazole inhibits ischemia-induced glutamate efflux from cerebral neurons. The first large controlled trial showed it to be well tolerated and suggested a clinically significant effect in patients with deficits of a major stroke.
J Stroke Cerebrovasc Dis 2000 Nov
PMID:Mechanisms of action of neuroprotectants in stroke. 1789 14

Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safety-feasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6h therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials. This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized.
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PMID:Neuroprotection for ischemic stroke: past, present and future. 1830 47

Neuronal cell death caused by pathophysiological over-activation of glutamate receptors and the subsequent CaII overloading, has been implicated in neurodegeneration after stroke, cerebral trauma and epileptic seizures. Recent findings suggest that certain progesterone metabolites (neurosteroids) such as allopregnanolone and dehydroepiandrosterone can protect neuronal cells from such insults. In the present study, murine P19 cells were induced to differentiate into postmitotic neurons expressing specific neuronal markers, including GABA(A) and NMDA receptors. Activation of NMDA receptors in P19-N neurons resulted in excitotoxic cell death, which involved suppression of the phosphorylation of the survival kinase PKB/Akt. Allopregnanolone and DHEA induced a rapid and prolonged phosphorylation of the Akt kinase and they were able to reverse the NMDA-induced suppression of the PI3-K/Akt pathway. The specificity of the neuroprotective effects of these neurosteroids was confirmed by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, as well as by the GABA(A) receptor antagonist, bicuculline. The neurotoxic effect of NMDA on P19-N neurons was directly correlated with increased CaII entry, since the addition of EGTA or BAPTA-AM, significantly suppressed the NMDA-induced decrease of phospho-Akt and subsequent neuronal death. These results suggest that neurosteroids are able to act as survival factors on P19-N neurons, promoting the activation of the PI3-K/Akt pathway through a calcium-entry dependent mechanism.
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PMID:Induction of Akt by endogenous neurosteroids and calcium sequestration in P19 derived neurons. 1852

Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.
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PMID:The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development. 1853 46

Cell therapy using bone marrow-derived mesenchymal stem cells (MSC) seems to be a new alternative for the treatment of neurological diseases, including stroke. In order to investigate the response of hippocampal tissue to factors secreted by MSC and if these factors are neuroprotective in a model of oxygen and glucose deprivation (OGD), we used organotypic hippocampal cultures exposed to conditioned medium from bone marrow-derived MSC. Our results suggest that the conditioned medium obtained from these cells aggravates lesion caused by OGD. In addition, the presence of the conditioned medium alone was toxic mainly to cells in the CA1, CA2 and CA3 areas of the hippocampal organotypic culture even in basal conditions. GABA stimulation and NMDA and AMPA receptors antagonists were able to reduce propidium iodide staining, suggesting that the cell death induced by the toxic factors secreted by MSC could involve these receptors.
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PMID:Conditioned medium from mesenchymal stem cells induces cell death in organotypic cultures of rat hippocampus and aggravates lesion in a model of oxygen and glucose deprivation. 1897 99

An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic interneurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status epilepticus induced by kainic acid. Using design-based stereology combined with glutamic acid decarboxylase (GAD) 67 immunohistochemistry, we found a more extensive loss of GABAergic interneurons compared to the loss of principal cells. Fluoro-Jade C staining showed that neuronal degeneration was still ongoing. These alterations were accompanied by an increase in the levels of GAD and the alpha1 subunit of the GABA(A) receptor, and a reduction in the GluK1 (previously known as GluR5) subunit, as determined by Western blots. Whole-cell recordings from BLA pyramidal neurons showed a significant reduction in the frequency and amplitude of action potential-dependent spontaneous inhibitory postsynaptic currents (IPSCs), a reduced frequency but not amplitude of miniature IPSCs, and impairment in the modulation of IPSCs via GluK1-containing kainate receptors (GluK1Rs). Thus, in the BLA, GABAergic interneurons are more vulnerable to seizure-induced damage than principal cells. Surviving interneurons increase their expression of GAD and the alpha1 GABA(A) receptor subunit, but this does not compensate for the interneuronal loss; the result is a dramatic reduction of tonic inhibition in the BLA circuitry. As activation of GluK1Rs by ambient levels of glutamate facilitates GABA release, the reduced level and function of these receptors may contribute to the reduction of tonic inhibitory activity. These alterations at a relatively early stage of epileptogenesis may facilitate the progress towards the development of epilepsy.
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PMID:Pathological alterations in GABAergic interneurons and reduced tonic inhibition in the basolateral amygdala during epileptogenesis. 1954 Mar 12

Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA(A) receptors, weak inhibitors of glutamate receptors and activators of some potassium channels. These pharmacological actions are all implicated in the pathogenesis of ischemic stroke. The aim of this study was to investigate the hypothesis that the fenamate, mefenamic acid, is neuroprotective in an in vitro and in vivo model of stroke. Embryonic rat hippocampal neurons were cultured and maintained for up to 14 days in vitro. At 9 or 14 days, cells were exposed to glutamate (5microM) or glutamate (5microM) plus mefenamic acid (10-100microM) or the control agent, MK-801 (10microM) for 10min. 24h later, cell death was determined by measuring lactate dehydrogenase (LDH) levels in the culture media. In vivo, male Wistar rats (300-350g) were subjected to 2h middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Animals received either a single i.v. dose of MFA (10mg/kg or 30mg/kg), or MK-801 (2mg/kg) or saline prior to MCAO or, four equal doses of MFA (20mg/kg) at 1h intervals beginning 1h prior to MCAO. Ischemic damage was then assessed 24h after MCAO. In vitro, mefenamic acid (10-100microM) and MK-801 (10microM) significantly reduced glutamate-evoked cell death compared with control cultures. In vivo, MFA (20mg/kgx4) significantly reduced infarct volume, total ischemic brain damage and edema by 53% (p< or =0.02), 41% (p< or =0.002) and 45% (p< or =0.002) respectively. Furthermore, mefenamic acid reduced cerebral edema when measured as a function of brain water content. MK-801 was also neuroprotective against MCAO brain injury. This study demonstrates a significant neuroprotective effect by a fenamate NSAID against glutamate-induced cell toxicity, in vitro and against ischemic stroke in vivo. Further experiments are currently addressing the mechanism(s) of this neuroprotection.
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PMID:Evidence for neuroprotection by the fenamate NSAID, mefenamic acid. 1956 51

Gamma aminobutyric acid (GABA) is an inhibitor neurotransmitter that plays many important roles in the central nervous system. Because the half-life time of GABA is very short in vivo, GABA itself is not used for clinical practice. An analogue of GABA, baclofen, is an agonist of GABA-B receptor, and has very strong antispastic effect by acting to the posterior horn of the spinal cord. However, baclofen poorly crosses through the blood brain barrier, and the antispastic effect is modest when administered orally. Therefore, direct continuous infusion of small doses of baclofen into the cerebrospinal fluid (intrathecal baclofen therapy, ITB) has become an established treatment for control of otherwise intractable severe spasticity. Spasticity is clinically defined as hypertonic state of the muscles with increased tendon reflexes, muscles spasm, spasm pain, abnormal posture, and limitation of involuntary movements. Spasticity is a common symptom after damage mainly to the pyramidal tract system in the brain or the spinal cord. Such damage is caused by traumatic brain injury, stroke, spinal cord injury, multiple sclerosis, and so on. Patients in persistent vegetative state (PVS) usually have diffuse and widespread damage to the brain, spasticity is generally seen in such patients. Control of spasticity may become important in the management of PVS patients in terms of nursing care, pain relief, and hygiene, and ITB may be indicated. Among PVS patients who had ITB to control spasticity, sporadic cases of dramatic recovery from PVS after ITB have been reported worldwide. The mechanism of such recovery of consciousness is poorly understood, and it may simply be a coincidence. On the other hand, electrical spinal cord stimulation (SCS) has been tried for many years in many patients in PVS, and some positive effects on recovery of consciousness have been reported. SCS is usually indicated for control of neuropathic pain, but it has also antispastic effect. The mechanism of SCS on pain is known to be mediated through the spinal GABA neuronal system. Thus, ITB and SCS have a common background, spinal GABA neuronal mechanism. The effect of GABA agonists on recovery of consciousness is not yet established, but review of such case studies becomes a clue to solve problems in PVS, and there may be hidden serendipity.
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PMID:Intrathecal administration of GABA agonists in the vegetative state. 1981 10

Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI and brain ischemia. Furthermore, more recently, some authors concluded that nonanticoagulant 3K3A-APC exhibits greater neuroprotective efficacy with no risk for bleeding compared with drotrecogin-alfa activated, a hyperanticoagulant form of APC. Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. Included in the sequence of events leading to neuronal death in ischemic tissue following stroke is an excessive and toxic rise in the intracellular Ca(2+)-concentration, predominantly due to an influx of Ca2+ through nonselective cation-channels as well as Ca(2+)-channels.. Some authros conducted a study to investigate whether the enhancement of GABA receptor activity could inhibit NMDA receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury. The results showed that both the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen had neuroprotective effect, and the combination of two agonists could significantly protect neurons against death induced by ischemia/reperfusion. On this basis we conclude that neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection.
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PMID:Neuron protection as a therapeutic target in acute ischemic stroke. 1984 59


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