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

Estrogen and progesterone are often thought of as steroid hormones that strongly influence reproductive and maternal behaviours. However, the steroids are now showing considerable promise as neuroprotective and neuroregenerative agents in stroke and traumatic brain injuries. Collectively, these two hormones have been reported to reduce the consequences of the injury cascade by enhancing anti-oxidant mechanisms, reducing excitotoxicity: altering glutamate receptor activity, reducing immune inflammation, providing neurotrophic support, stimulating axonal remyelinization and enhancing synaptogenesis and dendritic arborization. Estrogen has often been tried as a prophylactic treatment in females for ischemic brain injury, while progesterone has, thus far, been given as a post-injury treatment for both male and female subjects with acute, ischemic and traumatic injuries of the brain and spinal cord. This review compares and evaluates estrogen and progesterone as neuroactive agents in the acute treatment of brain damage caused by stroke and trauma.
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PMID:Estrogen and progesterone as neuroprotective agents in the treatment of acute brain injuries. 1274 91

Accumulated clinical and basic evidence suggests that gonadal steroids affect the onset and progression of several neurodegenerative diseases and schizophrenia, and the recovery from traumatic neurological injury such as stroke. Thus, our view on gonadal hormones in neural function must be broadened to include not only their function in neuroendocrine regulation and reproductive behaviors, but also to include a direct participation in response to degenerative disease or injury. Recent findings indicate that the brain up-regulates both estrogen synthesis and estrogen receptor expression at sites of injury. Genetic or pharmacological inactivation of aromatase, the enzyme involved in estrogen synthesis, indicates that the induction of this enzyme in the brain after injury has a neuroprotective role. Some of the mechanisms underlying the neuroprotective effects of estrogen may be independent of the classically defined nuclear estrogen receptors (ERs). Other neuroprotective effects of estrogen do depend on the classical nuclear ERs, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that non-classical ERs in the membrane or cytoplasm alter phosphorylation cascades, such as those involved in the signaling of insulin-like growth factor-1 (IGF-1). Indeed, ERs and IGF-1 receptor interact in the activation of PI3K and MAPK signaling cascades and in the promotion of neuroprotection. The decrease in estrogen and IGF-1 levels with aging may thus result in an increased risk for neuronal pathological alterations after different forms of brain injury.
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PMID:Estrogen and brain vulnerability. 1282 4

Testican-1 is a highly conserved, multidomain, chondroitin sulfate proteoglycan that is most abundantly transcribed in the brain by neurons. This testican messenger RNA is not detected in normal quiescent astrocytes, but is up regulated when these cells are activated in response to injury such as cerebral stroke. Other chondroitin sulfate proteoglycans found in glial scars, including neurocan, have been shown to inhibit neural cell attachment and neurite extensions and may thus impede axonal regeneration. Here we report the expression and purification of a proteoglycan form of recombinant testican and its effects on neuron-derived cells in culture. We demonstrate that testican inhibits attachment of Neuro-2a cells and their ability to form neurite extensions. Both testican proteoglycan and the core glycoprotein that has been depleted of chondroitin sulfate inhibit cell attachment. Pre-treatment of the culture substratum with testican inhibits Neuro-2a attachment, but pre-treatment of the cells with testican does not inhibit their attachment. Testican, therefore, blocks attachment sites on cultureware and may also block attachment sites in the extracellular matrix of the brain.
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PMID:Testican-1 inhibits attachment of Neuro-2a cells. 1285 36

The nitrone-based free radical scavengers have potent neuroprotective activities in models of stroke in which oxidative stress plays a key role in its development. We examined the effects of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide), a spin trap nitrone, on reperfusion injury in rat peripheral nerves. Immediately after the onset of 4-h ischaemia in rat right hindlimb, S-PBN was administered via mini-osmotic pumps, containing 2 ml of S-PBN (1.2 M), inserted subcutaneously. S-PBN, in addition, was given by a single injection (50 mg/kg BW, i.p.). Mean plasma concentrations of S-PBN were significantly greater in S-PBN-treated rats than in controls after 24, 48 and 72 h of reperfusion. Pump and dosing solution analysis indicated that the rats received between 82 and 99% of the target S-PBN concentration. Morphology in sciatic, tibial and peroneal nerves was assessed after 4 h of ischaemia followed by 72 h and 7 days of reperfusion. After 72 h of reperfusion, saline-treated control rats showed endoneurial oedema at the thigh level and diffuse axonal degeneration of myelinated nerve fibres distally. S-PBN-treated nerves were normal or revealed less severe abnormalities in myelinated fibres after 72 h and 7 days of reperfusion, when compared with those in saline-treated control nerves. Morphometrically, the frequency of abnormal myelinated fibres at calf levels was significantly less in S-PBN-treated nerves than in controls. In conclusion, post-ischaemic administration of S-PBN exhibits substantial neuroprotective properties in ischemia/reperfusion nerve injury.
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PMID:Neuroprotective effects of nitrone radical scavenger S-PBN on reperfusion nerve injury in rats. 1291 53

After a stroke, recovery that continues beyond 3 or 4 weeks has been attributed to plasticity, a reorganization of the brain in which functions previously performed by the ischemic area are assumed by other ipsilateral or contralateral brain areas. Neuronal plasticity has been variously attributed to redundancy (parallel distributed pathways), changes in synaptic strength, axonal sprouting with formation of new synapses, assumption of function by contralateral homologous cortex, and substitution of uncrossed pathways. Transcranial magnetic stimulation, positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and 128-electrode high-resolution electroencephalography have been successfully applied to demonstrate cortical reorganization after hemiplegia. Recording the motor potential is a promising noninvasive method for the localization of motor control after hemispheric lesions. Most patients with hemiparetic stroke show some improvement, usually during the first 3 to 6 months after the ictus. Improvement and prognosis depend on a number of variables including volume and location of the infarction, age of the patient, and the elimination of risk factors to avoid future episodes (i.e., dietary control of lipids, the elimination of tobacco, and the control of diabetes and hypertension). Currently, emphasis has been placed on fibrinolytic treatment in the first 3 hours to prevent or minimize neurological deficit. Aside from the above listed factors, improvement after stroke may be due to reorganization of the brain, particularly the cerebral cortex, and repair of damaged tissue and recanalization. It is also important to relate such changes to functional improvement and successful rehabilitation.
Top Stroke Rehabil 2003
PMID:Brain reorganization after stroke. 1468 16

NMDA receptor antagonists have been investigated for many years as therapeutic agents for the treatment of neurological disorders such as stroke, epilepsy, pain and Parkinson's disease. It has been discovered, however, that many of these compounds cause adverse behavioral (psychotomimetic) effects and can produce neurotoxicity characterized by neuronal vacuolization, induction of heat-shock protein, neuronal/axonal degeneration and regional brain cell death in several animal species. It is unknown whether NMDA antagonists induce neurotoxicity in humans. The mechanism of NMDA antagonist-induced neurotoxicity is not completely known, but some evidence suggests disinhibition of GABAergic inputs to the affected neurons. Several classes of compounds have been shown to prevent NMDA antagonist-induced neurotoxicity. The extent of neurotoxicity produced by NMDA antagonists is affected by many factors, including type of antagonist, dose, length of exposure, age, sex and species. While there are no published regulatory guidelines regarding how NMDA antagonist compounds should be evaluated, sponsors and investigators of these compounds should make every effort to assess the potential for neurotoxicity. NMDA receptor antagonists, as well as other CNS-active compounds need to be analyzed for neurotoxicity through careful experimental design, adequate tissue sampling and through the use of a sensitive method of detection.
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PMID:Review of NMDA antagonist-induced neurotoxicity and implications for clinical development. 1475 81

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP). Apoptosis-inducing factor (AIF) is a flavoprotein that is normally confined to the mitochondria, but translocates to the nucleus, as shown by in vitro models of neuronal injury. Using INO-1001, a novel potent inhibitor of PARP, we determined the role of PARP activation in the process of AIF translocation in a rat model of focal cerebral ischemia. The potency of INO-1001 as a PARP inhibitor and its cytoprotective potential in oxidant-challenged human neuronal SK-N-MC cells was first confirmed in vitro. PARP inhibition markedly reduced infarct size and improved neurological status in both transient and permanent models of MCA occlusion in Sprague-Dawley rats, with a therapeutic window of 6 h and 2 h in the transient and permanent ischemia models, respectively. The PARP inhibitor reduced the accumulation of poly(ADP-ribose) in the ischemic/reperfused hemisphere and reduced the accumulation of APP in the white matter of the affected hemisphere, consistently with protection against neuronal necrosis and axonal damage, respectively. Immunohistochemical analysis showed the appearance of AIF labeling in neuronal nuclei of the border zone ischemic area in the striatum after stroke. Cytoplasmatic (axonal) AIF staining was significantly diminished in the necrotic core of the striatum, while it was somewhat enhanced at the borderline ischemic territories of the white matter. Inhibition of PARP with INO-1001 reshifted the location of the apoptotic marker to the axons in the ipsilateral striatum. Thus, PARP inhibition is neuroprotective and regulates the ischemic nuclear translocation of AIF in stroke.
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PMID:Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. 1476 66

Hypertension is one of the major risk factors of stroke and vascular dementia (VaD). We used stroke prone spontaneous hypertensive rats (SPSHRs) as a model for neuronal degeneration frequently occurring in humans with vascular disease. Recently, high b value q-space diffusion-weighted imaging (DWI) was shown to be very sensitive to the pathophysiological state of the white matter. We studied the spinal cords of SPSHR rats ex vivo after the appearance of motor impairments using diffusion anisotropy and q-space diffusion imaging (measured at a high b value of up to 1 x 10(5) s/mm(2)). The diffusion anisotropy images computed from low b value data set (b(max) approximately 2500 s/mm(2)) showed a small but statistically significant decrease (approximately 12%, P < 0.05) in the diffusion anisotropy in the spinal cords of the SPSHR group as compared to control rats. However, more significant changes were found in the high b value q-space diffusion images. The q-space displacement values in the white matter of the SPSHR group were found to be higher by more than 70% (P < 0.002) than that of the control group. These observations concurred with electron microscopy (EM) that showed significant demyelination in the spinal cords of the SPSHR group. These results seem to indicate that high b value q-space DWI might be a sensitive method for following demyelination and axonal loss associated with vascular insults.
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PMID:Hypertension and neuronal degeneration in excised rat spinal cord studied by high-b value q-space diffusion magnetic resonance imaging. 1476 64

In the past, neuroprotective therapies were mostly explored in neurodegenerative disorders like Parkinson's and Alzheimer's disease, and in ischaemic stroke. More recently, however, neuroprotection has been proclaimed an important goal for multiple sclerosis (MS) therapy. The basis for widening the scope of neuroprotection is evidence that neuronal and axonal injury are key features of MS lesions. In contrast with degenerative and ischaemic central nervous system injury, however, neurodegeneration in MS appears to be caused by an inflammatory, presumably autoimmune, process. The challenge for neuroprotection in MS is therefore greater than in degenerative and ischaemic disorders, because MS requires the combination of neuroprotective therapy and effective immunomodulation.
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PMID:The prospects for neuroprotection in MS. 1497 85

White matter of the brain and spinal cord is susceptible to anoxia, ischemia, trauma and autoimmune attack. Irreversible injury to this tissue can have serious consequences for the overall function of the CNS through disruption of signal transmission. Like neurons, central myelinated axons are critically dependent on a continuous supply of oxygen and glucose. Injury causes failure of the Na-K-ATPase and accumulation of axoplasmic Na through non-inactivating Na channels, which, together with membrane depolarization, promotes reverse Na-Ca exchange and axonal Ca overload. An equally important source of deleterious Ca originates from intracellular stores, released in part by a mechanism similar to "excitation-contraction coupling" in muscle, involving activation of ryanodine receptors by L-type Ca channels. Excitotoxic mechanisms also play an important role: glutamate released by reversal of Na-dependent glutamate transporters activates AMPA/kainate receptors to cause injury to glia and myelin. Excessive accumulation of cytosolic Ca in turn activates various Ca-dependent enzymes such as calpains, phospholipases and others resulting in irreversible injury. Reoxygenation paradoxically accelerates injury in many axons, and promotes cytoskeletal degradation. Blockers of voltage-gated Na channels represent an attractive therapeutic target because of their ability to simultaneously interfere indirectly with several Ca sourcing pathways. Alternatively, or additionally, AMPA/kainate receptor inhibition has also been shown to be neuroprotective in several white matter injury paradigms. In the clinical setting, optimal protection of the CNS as a whole in common disorders such as stroke, traumatic brain and spinal cord injury, will likely require combination therapy aimed at unique steps in gray and white matter regions, or intervention at common points in the injury cascades.
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PMID:White matter injury mechanisms. 1503 8


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