Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.
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PMID:Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. 905 Aug 95

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.
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PMID:Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. 939 Jun 45

Tumor necrosis factor-alpha (TNF-alpha) expression has been documented extensively in animal models of traumatic spinal cord injury (SCI). However, the pathophysiological significance of TNF-alpha expression in the injured cord remains to be delineated. The TNF receptor (TNFR)-nuclear factor-kappaB (NF-kappaB) signal transduction pathway is important for maintaining cell viability. NF-kappaB exerts anti-apoptotic effects via an endogenous caspase inhibitory system mediated by cellular inhibitor of apoptosis protein 2 (c-IAP2). NF-kappaB transactivates c-IAP2 to inhibit caspase-3 activation. Progressive cell death, including morphological and biochemical features suggestive of apoptosis, has been noted after SCI. We explored the effects of TNFR1 or TNFR2 deletion on the apoptotic events downstream of NF-kappaB in relation to SCI pathology and functional recovery. Nuclear proteins from the injured cords of the TNFR1(-/-) mice had a reduced NF-kappaB binding activity compared with the wild-type controls. This decrease in NF-kappaB activation was accompanied by a reduction in c-IAP2 expression and an increase in the active form of caspase-3 protein. After SCI the TNFR1(-/-) mice had greater numbers of apoptotic cells, a larger lesion size, and worse functional recovery than wild-type mice. TNFR2-deficient mice had a similar, although not as pronounced, consequence as the TNFR1(-/-) mice. These findings support the argument that the TNFR-NF-kappaB pathway is beneficial for limiting apoptotic cell death after SCI and that a defective TNFR-NF-kappaB pathway results in a poorer neurological outcome. A worse functional outcome in TNFR(-/-) mice suggests that an endogenous apoptosis inhibitory mechanism mediated by TNFR activation, NF-kappaB, and c-IAP2 may be of pathophysiological importance.
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PMID:Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. 1151 51

Traumatic brain injury (TBI) is a serious neurodisorder commonly caused by car accidents, sports related events or violence. Preventive measures are highly recommended to reduce the risk and number of TBI cases. The primary injury to the brain initiates a secondary injury process that spreads via multiple molecular mechanisms in the pathogenesis of TBI. The events leading to both neurodegeneration and functional recovery after TBI are generalized into four categories: (i) primary injury that disrupts brain tissues; (ii) secondary injury that causes pathophysiology in the brain; (iii) inflammatory response that adds to neurodegeneration; and (iv) repair-regeneration that may contribute to neuronal repair and regeneration to some extent following TBI. Destructive multiple mediators of the secondary injury process ultimately dominate over a few intrinsic protective measures, leading to activation of cysteine proteases such as calpain and caspase-3 that cleave key cellular substrates and cause cell death. Experimental studies in rodent models of TBI suggest that treatment with calpain inhibitors (e.g., AK295, SJA6017) and neurotrophic factors (e.g., NGF, BDNF) can prevent neuronal death and dysfunction in TBI. Currently, there is still no precise therapeutic strategy for the prevention of pathogenesis and neurodegeneration following TBI in humans. The search continues to explore new therapeutic targets and development of promising drugs for the treatment of TBI.
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PMID:Molecular mechanisms in the pathogenesis of traumatic brain injury. 1237 Nov 42

The hypothesis was tested that hyperbaric oxygen therapy (HBO) reduced brain infarction by preventing apoptotic death in ischemic cortex in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and subsequently were exposed to HBO (2.5 atmospheres absolute) for 2 h, at 6 h after reperfusion. Rats were killed and brain samples were collected at 24, 48, 72 h, and 7 days after reperfusion. Neurologic deficits, infarction area, and apoptotic changes were evaluated by clinical scores, 2,3,7-triphenyltetrazolium chloride staining, caspase-3 expression, DNA fragmentation assay, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL)-hematoxylin and eosin (H&E) costaining. In MCAO/R without HBO treatment animals, DNA fragmentation was observed in injured cortex at 24, 48, and 72 h but not in samples at 7 days after reperfusion. Double labeling of brain slides with NeuN and caspase-3 demonstrated neurons in the injured cortex labeled with caspase-3. TUNEL+H&E costaining revealed morphologic apoptotic changes at 24, 48, and 72 h after reperfusion. Hyperbaric oxygen therapy abolished DNA fragmentation and reduced the number of TUNEL-positive cells. Hyperbaric oxygen therapy reduced infarct area and improved neurologic scores at 7 days after reperfusion. One of the molecular mechanisms of HBO-induced brain protection is to prevent apoptosis, and this effect of HBO might preserve more brain tissues and promote neurologic functional recovery.
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PMID:Inhibition of apoptosis by hyperbaric oxygen in a rat focal cerebral ischemic model. 1284 89

Acupuncture has been used for the enhancement of functional recovery from various disorders including stroke. In the present study, the effects of acupuncture on the c-Fos expression and apoptosis in the hippocampal CA1 region of gerbils following transient global ischemia were investigated via immunohistochemistry for c-Fos and caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Enhanced Fos, TUNEL, and caspase-3 positivities were detected in the hippocampal CA1 region in the ischemic gerbils. Acupunctural treatment suppressed the ischemia-induced increment in the number of Fos-, TUNEL-, and caspase-3-positive cells: the most potent suppressive effect was observed at the Zusanli acupoint. These results suggest that acupunctural treatment alleviates ischemia-induced apoptosis and may aid in the recovery following ischemic cerebral injury.
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PMID:Acupuncture suppresses ischemia-induced increase in c-Fos expression and apoptosis in the hippocampal CA1 region in gerbils. 1286 28

We examined the effects of minocycline, an anti-inflammatory drug, on functional recovery following spinal cord injury (SCI). Rats received a mild, weight-drop contusion injury to the spinal cord and were treated with the vehicle or minocycline at a dose of 90 mg/kg immediately after SCI and then twice at a dose of 45 mg/kg every 12 h. Injecting minocycline after SCI improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Twenty four to 38 days after SCI, BBB scores were significantly higher in minocycline-treated rats as compared with those in vehicle-treated rats. Morphological analysis showed that lesion size increased progressively in both vehicle-treated and minocycline-treated spinal cords. However, in response to treatment with minocycline, the lesion size was significantly reduced at 21-38 days after SCI when compared to the vehicle control. Minocycline treatment significantly reduced the number of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive cells 24 h after SCI as compared to that of the vehicle control. DNA gel electrophoresis also revealed a marked decrease in DNA laddering in response to treatment with minocycline. In addition, minocycline treatment significantly reduced the specific caspase-3 activity after SCI as compared to that of vehicle control. Furthermore, RT-PCR analyses revealed that minocycline treatment increased expression of interleukin-10 mRNA but decreased tumor necrosis factor-alpha expression. These data suggest that, after SCI, minocycline treatment modulated expression of cytokines, attenuated cell death and the size of lesions, and improved functional recovery in the injured rat. This approach may provide a therapeutic intervention enabling us to reduce cell death and improve functional recovery after SCI.
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PMID:Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. 1458 18

Necrosis and apoptosis differentially contribute to myocardial injury. Determination of the contribution of these processes in ischemia-reperfusion injury would allow for the preservation of myocardial tissue. Necrosis and apoptosis were investigated in Langendorff-perfused rabbit hearts (n = 47) subjected to 0 (Control group), 5 (GI-5), 10 (GI-10), 15 (GI-15), 20 (GI-20), 25 (GI-25), and 30 min (GI-30) of global ischemia (GI) and 120 min of reperfusion. Myocardial injury was determined by triphenyltetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), bax, bcl2, poly(ADP)ribose polymerase (PARP) cleavage, caspase-3, -8, and -9 cleavage and activity, Fas ligand (FasL), and Fas-activated death domain (FADD). The contribution of apoptosis was determined separately (n = 42) using irreversible caspase-3, -8, and -9 inhibitors. Left ventricular peak developed pressure (LVPDP) and systolic shortening (SS) were significantly decreased and infarct size and TUNEL-positive cells were significantly increased (P < 0.05 vs. Control group) at GI-20, GI-25, and GI-30. Proapoptotic bax, PARP cleavage, and caspase-3 and -9 cleavage and activity were apparent at GI-5 to GI-30. Fas, FADD, and caspase-8 cleavage and activity were unaltered. Irreversible inhibition of caspase-3 and -9 activity significantly decreased (P < 0.05) infarct size at GI-25 and GI-30 but had no effect on LVPDP or SS. Myocardial injury results from a significant increase in both necrosis and apoptosis (P < 0.05 vs. Control group) evident by TUNEL, TTC staining, and caspase activity at GI-20. Intrinsic proapoptotic activation is evident early during ischemia but does not significantly contribute to infarct size before GI-25. The contribution of necrosis to infarct size at GI-20, GI-25, and GI-30 is significantly greater than that of apoptosis. Apoptosis is significantly decreased by caspase inhibition during early reperfusion, but this protection does not improve immediate postischemic functional recovery.
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PMID:Differential contribution of necrosis and apoptosis in myocardial ischemia-reperfusion injury. 1471 9

Overactivation of proteases play a key role in the development of ischemia reperfusion (IR) myocardial injury. Calpains are calcium-dependent cysteine proteases and have been implicated in post-ischemic cell death. Moreover, activation of caspases, another family of proteases, represents an important step in the apoptotic process. We investigated the effect of leupeptin and calpain inhibitor-1 (CAI-1), two calpain inhibitors and of a caspase-3 inhibitor, Ac-DEVD-CHO, on functional recovery, myocardial infarct size and apoptosis in isolated rat hearts (Langendorff technique) subjected to 30 min of global ischemia and 120 min of reperfusion. Each inhibitor was added to the perfusion medium 10 min before ischemia and during the first 30 min of reperfusion. IR was associated with mechanical dysfunction and myocardial infarction. Apoptosis induced by this sequence was demonstrated by DNA ladder and TUNEL staining. Whereas leupeptin, CAI-1 or Ac-DEVD-CHO did not modify post-ischemic function, they significantly reduced infarct size and cardiomyocyte positive TUNEL staining. Our findings suggest that calpain and caspase-3 inhibitors may protect heart from the development of cell death induced by IR; this effect could be due, at least in part, to the reduction of apoptosis. However, in our experimental conditions, these inhibitors did not afford improvement of post-ischemic myocardial function.
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PMID:Calpain and caspase-3 inhibitors reduce infarct size and post-ischemic apoptosis in rat heart without modifying contractile recovery. 1499 81

Recent evidence indicates that estrogen exerts neuroprotective effects in both brain injury and neurodegenerative diseases. We examined the protective effect of estrogen on functional recovery after spinal cord injury (SCI) in rats. 17beta-estradiol (3, 100, or 300 microg/kg) was administered intravenously 1-2 h prior to injury (pre-treatment), and animals were then subjected to a mild, weight-drop spinal cord contusion injury. Estradiol treatment significantly improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Fifteen to 30 days after SCI, BBB scores were significantly higher in estradiol-treated (100 microg/kg) rats when compared to vehicle-treated rats. Morphological analysis showed that lesion sizes increased progressively in either vehicle-treated or 17beta-estradiol-treated spinal cords. However, in response to treatment with 17beta-estradiol, the lesion size was significantly reduced 18-28 days after SCI when compared to vehicle-treated controls. Terminal deoxynucleotidyl transferase-mediated UTP nickend labeling (TUNEL) staining and DNA gel electrophoresis revealed that apoptotic cell death peaked 24-48 h after injury. Also, SCI induced a marked increase in activated caspase-3 in the spinal cord, evident by 4 h after injury. However, administration of 17beta-estradiol significantly reduced the SCI-induced increase in apoptotic cell death and caspase-3 activity after SCI. Furthermore, 17beta-estradiol significantly increased expression of the anti-apoptotic genes, bcl-2 and bcl-x, after SCI while expression of the pro-apoptotic genes, bad and bax, was not affected by drug treatment. Finally, intravenous administration of 17beta-estradiol (100 microg/kg) immediately after injury (post-treatment) also significantly improved hind limb motor function 19-30 days after SCI compared to vehicle-treated controls. These data suggest that after SCI, 17 beta-estradiol treatment improved functional recovery in the injured rat, in part, by reducing apoptotic cell death.
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PMID:Systemic administration of 17beta-estradiol reduces apoptotic cell death and improves functional recovery following traumatic spinal cord injury in rats. 1511 4


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