Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein activated by DNA nicks, mediates cell death in vitro by nicotinamide adenine dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition by 3-aminobenzamide (3-AB) attenuates tissue injury after transient cerebral ischemia. Twenty-two hours after reperfusion following 2 hours of filamentous middle cerebral artery occlusion, ischemic injury was decreased in PARP-/- and PARP+/- mice compared with PARP+/+ litter mates, and also was attenuated in 129/SV wild-type mice after 3-AB treatment compared with controls. Infarct sparing was accompanied by functional recovery in PARP-/- and 3-AB-treated mice. Increased poly(ADP-ribose) immunostaining observed in ischemic cell nuclei 5 minutes after reperfusion was reduced by 3-AB treatment. Levels of NAD--the substrate of PARP--were reduced 2 hours after reperfusion and were 35% of contralateral levels at 24 hours. The decreases were attenuated in PARP-/- mice and in 3-AB-treated animals. Poly(ADP-ribose)polymerase cleavage by caspase-3 (CPP-32) has been proposed as an important step in apoptotic cell death. Markers of apoptosis, such as oligonucleosomal DNA damage, total DNA fragmentation, and the density of terminal deoxynucleotidyl transferase dUTP nick-end-labelled (TUNEL +) cells, however, did not differ in ischemic brain tissue of PARP-/- mice or in 3-AB-treated animals versus controls, although there were differences in the number of TUNEL-stained cells reflecting the decrease in infarct size. Thus, ischemic brain injury activates PARP and contributes to cell death most likely by NAD depletion and energy failure, although the authors have not excluded a role for PARP in apoptotic cell death at earlier or later stages in ischemic cell death. Inhibitors of PARP activation could provide a potential therapy in acute stroke.
 ...
PMID:Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. 939 Jun 45

In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
 ...
PMID:Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. 1020 88

This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.
 ...
PMID:[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy]. 1020 84

A number of studies have provided evidence that neuronal cell loss after stroke involves programmed cell death or apoptosis. In particular, recent biochemical and immunohistochemical studies have demonstrated the expression and activation of intracellular proteases, notably caspase-3, which act as both initiators and executors of the apoptotic process. To further elucidate the involvement of caspases in neuronal cell death induced by focal stroke we developed a panel of antibodies and investigated the spatial and temporal pattern of both caspase-8 and caspase-3 expression. Our efforts focused on caspase-8 because its "apical" position within the enzymatic cascade of caspases makes it a potentially important therapeutic target. Constitutive expression of procaspase-8 was detectable in most cortical neurons, and proteolytic processing yielding the active form of caspase-8 was found as early as 6 hr after focal stroke induced in rats by permanent middle cerebral artery occlusion. This active form of caspase-8 was predominantly seen in the large pyramidal neurons of lamina V. Active caspase-3 was evident only in neurons located within lamina II/III starting at 24 hr after injury and in microglia throughout the core infarct at all times examined. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, gel electrophoresis of DNA, and neuronal cell quantitation indicated that there was an early nonapoptotic loss of cortical neurons followed by a progressive elimination of neurons with features of apoptosis. These data indicate that the pattern of caspase expression occurring during delayed neuronal cell death after focal stroke will vary depending on the neuronal phenotype.
 ...
PMID:Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. 1040 32

Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.
 ...
PMID:High level calcineurin activity predisposes neuronal cells to apoptosis. 1056 26

Caspase-9 is a member of caspase family of cysteine proteases that have been implicated in apoptosis and cytokine processing. When cells receive apoptotic stimuli, mitochondria releases cytochrome c which then binds to Apaf-1, the mammalian Ced-4 homologue, together with dATP. The resultant complex recruits Caspase-9 leading to its activation. Activated Caspase-9 cleaves downstream caspases such as Caspase-3, -6 and -7 initiating the caspase cascade. The majority of homozygous Caspase-9 null mice die perinatally with a markedly enlarged and malformed cerebrum caused by a reduction of apoptosis during early brain development. Thus, Caspase-9 function is essential for apoptosis during normal development of the central nervous system. These data suggest that inhibition of Caspase-9 activity would render opportunity to treat patients suffering from neurological diseases such as stroke, neurodegenerative diseases or brain injury caused by hypoxia.
 ...
PMID:Caspase-9. 1068 48

Accumulating evidence strongly suggests that apoptosis contributes to neuronal cell death in a variety of neurodegenerative contexts. Activation of the cysteine protease caspase-3 appears to be a key event in the execution of apoptosis in the central nervous system (CNS). As a result, mice null for caspase-3 display considerable neuronal expansion usually resulting in death by the second week of life. At present, 14 caspase family members have been identified and subdivided into three subgroups on the basis of preference for specific tetrapeptide motifs using a positional scanning combinatorial substrate library. Caspase-3 is a group II member (2, 3, 7) categorized by an absolute substrate requirement for aspartic acid in the P4 position of the scissile bond. The preferred cleavage motif (DExD) for group II caspases is found in many structural, metabolic and repair proteins essential for cellular homeostasis. Consistent with the proposal that apoptosis plays a central in role human neurodegenerative disease, caspase-3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzheimer's disease. Indeed, peptide-based caspase inhibitors prevent neuronal loss in animal models of head injury and stroke suggesting that these compounds may be the forerunners of non-peptide small molecules that halt apoptosis processes implicated in these neurodegenerative disorders. A clear link between an hereditary neurodegenerative disorder and failed caspase inhibition has recently been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal specific inhibitor of apoptosis (IAP) family member known as NAIP is often dysfunctional due to missense and truncation mutations. IAPs such as NAIP potently block the enzymatic activity of group II caspases (3 and 7) suggesting that NAIP mutations may permit unopposed developmental apoptosis to occur in sensory and motor systems resulting in lethal muscular atrophy. Conversely, adenovirally-mediated overexpression of NAIP or the X-linked IAP called XIAP reduces the loss of CA1 hippocampal neurons following transient forebrain ischemia. Taken together, these findings suggest that anti-apoptotic strategies may some day have utility in the treatment of neurodegenerative disease. The present review will summarize some of the recent evidence suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditions.
 ...
PMID:Neuroprotection by the inhibition of apoptosis. 1076 48

Caspase-11, a member of the murine caspase family, has been shown to be an upstream activator of caspase-1 in regulating cytokine maturation. We demonstrate here that in addition to its defect in cytokine maturation, caspase-11-deficient mice have a reduced number of apoptotic cells and a defect in caspase-3 activation after middle cerebral artery occlusion (MCAO), a mouse model of stroke. Recombinant procaspase-11 can autoprocess itself in vitro. Purified active recombinant caspase-11 cleaves and activates procaspase-3 very efficiently. Using a positional scanning combinatorial library method, we found that the optimal cleavage site of caspase-11 was (I/L/V/P)EHD, similar to that of upstream caspases such as caspase-8 and -9. Our results suggest that caspase-11 is a critical initiator caspase responsible for the activation of caspase-3, as well as caspase-1 under certain pathological conditions.
 ...
PMID:Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. 1079 75

Glutamate receptor overactivation contributes to neuron death after stroke, trauma, and epileptic seizures. Exposure of cultured rat hippocampal neurons to the selective glutamate receptor agonist N-methyl-d-aspartate (300 microm, 5 min) or to the apoptosis-inducing protein kinase inhibitor staurosporine (300 nm) induced a delayed neuron death. In both cases, neuron death was preceded by the mitochondrial release of the pro-apoptotic factor cytochrome c. Unlike staurosporine, the N-methyl-d-aspartate-induced release of cytochrome c did not lead to significant activation of caspase-3, the main caspase involved in the execution of neuronal apoptosis. In contrast, activation of the Ca(2+)-activated neutral protease calpain I was readily detectable after the exposure to N-methyl-d-aspartate. In a neuronal cell-free apoptosis system, calpain I prevented the ability of cytochrome c to activate the caspase cascade by inhibiting the processing of procaspase-3 and -9 into their active subunits. In the hippocampal neuron cultures, the inhibition of calpain activity restored caspase-3-like protease activity after an exposure to N-methyl-d-aspartate. Our data demonstrate the existence of signal transduction pathways that prevent the entry of cells into a caspase-dependent cell death program after the mitochondrial release of cytochrome c.
 ...
PMID:Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death. 1082 77

As a model of the reperfusion injury found in stroke, we have exposed neurons to hypoxia followed by reoxygenation. Neurons treated with hypoxia/reoxygenation (H/R) respond by activating nuclear factor-kappaB (NFkappaB), releasing cytochrome c from their mitochondria, and ultimately dying. Further supporting an apoptotic mechanism, expression of the antiapoptotic Bcl-2 and Bcl-x proteins was increased following H/R. In this model, adenoviral-mediated transduction of lkappaB expression inhibited NFkappaB activation and significantly accelerated cytochrome c release and caspase-dependent neuronal death. At the same time, expression of mutated lkappaB prevented the increased expression of endogenous Bcl-2 and Bcl-x. In the presence of mutated lkappaB, singular overexpression of only Bcl-2 by adenoviral-mediated transduction significantly inhibited cytochrome c release, caspase-3-like activation, and cell death in response to H/R. These findings suggest a pathway where NFkappaB activation induces overexpression of Bcl-2 and Bcl-x, which function to prevent apoptotic cell death following H/R treatments.
 ...
PMID:A pathway of neuronal apoptosis induced by hypoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2. 1089 43


1 2 3 4 5 6 7 8 9 10 Next >>