Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed treatment with nicotinamide (NAm) protects male rats against cerebral ischemia. Since the preponderant use of male animals in stroke research may produce results not applicable to female stroke patients due to gender-related differences, we examined whether delayed NAm treatment could protect female rats against focal cerebral ischemia using a model of permanent middle cerebral artery occlusion (MCAo). NAm (500 mg/kg) given intravenously, 2 h after MCAo, significantly reduced the infarct volume of female Sprague-Dawley (55%, P<0.05) and Wistar rats (60%, P<0.05) rats when compared with saline-injected controls. These studies confirm that NAm is neuroprotective specifically at the dose of 500 mg/kg in rats. The novel findings are that this neuroprotection occurs in female, as well as male rats, and that the neuroprotection observed is more robust when administered as an intravenous bolus compared with intraperitoneal administration.
 ...
PMID:Post-treatment with nicotinamide (vitamin B(3)) reduces the infarct volume following permanent focal cerebral ischemia in female Sprague-Dawley and Wistar rats. 1070 55

Gp91-phox is an integral component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex that generates reactive oxygen species (ROS) in activated circulating phagocytes. The authors previously demonstrated that gp91-phox knockout (KO) mice show significant protection from neuronal injury after cerebral ischemia--reperfusion injury, suggesting a pivotal role for this enzyme. Moreover, results from chimeric mice suggested that elimination of gp91-phox from both circulating phagocytes and a putative central nervous system (CNS) source were required to confer neuroprotection. In the current study, the authors demonstrated gp91-phox-specific immunostaining of perivascular cells in the CNS of control rats. However, after transient cerebral ischemia, gp91-phox-positive phagocytes were observed within the core ischemic region and activated microglial cells were positive in the penumbra. Such activated microglial cells were also gp91-phox-positive in the CNS of a chimpanzee with mild meningitis. Finally, in humans, both normal adult CNS tissues and isolated fetal microglial cells expressed gp91-phox mRNA. These microglia also expressed mRNA for the five other known components that comprise the NADPH oxidase complex. These data strongly suggest that microglial cells may contain a functionally active NADPH oxidase capable of generating ROS during CNS inflammation.
 ...
PMID:Induction of gp91-phox, a component of the phagocyte NADPH oxidase, in microglial cells during central nervous system inflammation. 1132 23

A single, delayed dose of nicotinamide (NAm) was shown to be protective against focal cerebral ischemia in rats, but the protection was limited to three to seven days following stroke. The investigation reported here was conducted to examine if the use of multiple doses of NAm, administered after the onset of focal cerebral ischemia, would extend the duration of neuroprotection compared with a single dose treatment regimen. Male Wistar rats were subjected to transient focal cerebral ischemia by occluding the right middle cerebral artery (MCAo) for two hours. Following MCAo, motor and sensory behavioral tests were performed daily and the cerebral infarct volumes were measured at two weeks after sacrifice. Each animal was placed into one of four groups that received either normal saline alone (Group S), one (Group A), two (Group B), or three (Group C) doses of NAm (500 mg/kg). Each animal, therefore, received three treatments over two weeks, with the first dose administered intravenously two hours after the onset of MCAo. Single and multiple doses of NAm reduced the infarction (p < 0.01) and improved (p < 0.05) the neurologic sensory and motor behavior when compared with the saline-treated animals up to two weeks after stroke. Moreover, animals that received multiple doses of NAm recuperated full motor function not different from normal, preoperative motor behavior. Delayed treatment with NAm given as multiple doses, therefore, further enhances the extent and duration of neuroprotection by significantly reducing cerebral infarct volumes, improving neurologic behavioral scores, and confers a complete motor recovery up to two weeks from the onset of focal cerebral ischemia in Wistar rats.
 ...
PMID:Delayed multidose treatment with nicotinamide extends the degree and duration of neuroprotection by reducing infarction and improving behavioral scores up to two weeks following transient focal cerebral ischemia in Wistar rats. 1146 97

Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is known as a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. It is also called poly(ADP-ribose) synthase (PARS) or poly(ADP-ribose) transferase (PADRT). In physiological conditions, PARP plays an important role in maintaining genomic stability. However, for several pathological situations, which include massive DNA injury (brain ischemia for example), excessive activation of PARP can deplete stores of nicotinamide adenine dinucleotide (NAD+), the PARP substrate, which, with the subsequent ATP depletion, leads to cell death. PARP activation appears to play a major role in neuronal death induced by cerebral ischemia, traumatic brain injury, Parkinson disease and other pathologies. PARP inhibitors (3-aminobenzamide and other compounds) and PARP gene deletion induced dramatic neuroprotection in experimental animals (rats, mice). Accordingly, these data suggest that PARP inhibitors could provide a novel therapeutic approach in a wide range of neurodegenerative disorders including cerebral ischemia and traumatic brain injury.
 ...
PMID:[Neuronal death: potential role of the nuclear enzyme, poly (ADP-ribose) polymerase]. 1150 Dec 63

The therapeutic window with the neuroprotectant nicotinamide (NAm) was tested in a model of stroke. Either 2, 4 or 6 h after the onset of transient (2 h) focal cerebral ischemia, Wistar rats received either saline or NAm (500 mg/kg). Sensory and motor behavioral scores and weight of the animals were obtained before surgery, and 2 h, 3 and 7 days after stroke onset. Cerebral infarct volumes were measured on day 7 after sacrifice. NAm given 4 or 6 h after stroke onset significantly (p<0.05) reduced the cerebral infarction and improved the behavioral scores, respectively, compared to saline-injected animals. There was a non-significant improvement in weight gained by NAm-treated rats at 3 and 7 days following stroke compared to the saline-injected controls.
 ...
PMID:Therapeutic window for nicotinamide following transient focal cerebral ischemia. 1189 12

Since hypertension and/or hyperglycemia are risk factors for stroke, we examined whether the putative neuroprotectant, nicotinamide (NAm), could protect spontaneously hypertensive rats (SHR) or diabetic Fischer 344 rats against focal cerebral ischemia using a model of permanent middle cerebral artery occlusion (MCAo). Intravenous NAm given 2 h after MCAo significantly reduced the infarct volume of SHR (750 mg/kg, 31%, P<0.01) and diabetic (500 mg/kg, 56%, P<0.01) as well as non-diabetic (500 mg/kg, 73%, P<0.01) Fischer 344 rats when compared with saline-injected controls. Thus delayed treatment with NAm protected hypertensive and hyperglycemic rats against a robust model of stroke.
 ...
PMID:Delayed treatment with nicotinamide (vitamin B3) reduces the infarct volume following focal cerebral ischemia in spontaneously hypertensive rats, diabetic and non-diabetic Fischer 344 rats. 1189 90

We investigated the neuroprotective action of nicotinamide in focal ischemia. Male spontaneously hypertensive rats (5-7 months old) were subjected to photothrombotic occlusion of the right distal middle cerebral artery (MCA). Either nicotinamide (125 or 250 mg/kg) or vehicle was injected i.v. before MCA occlusion. Changes in the cerebral blood flow (CBF) were monitored using laser-Doppler flowmetry, and infarct volumes were determined with TTC staining 3 days after MCA occlusion. In another set of experiments, the brain nicotinamide and nicotinamide adenine dinucleotide (NAD+) levels were analyzed by HPLC using the frozen samples dissected from the regions corresponding to the ischemic core and penumbra. In the 250-mg/kg nicotinamide group, the ischemic CBF was significantly increased compared to that the untreated group, and the infarct volumes were substantially attenuated (-36%). On the other hand, the ischemic CBF in the 125 mg/kg nicotinamide group was not significantly different from the untreated CBF, however, the infarct volumes were substantially attenuated (-38%). Cerebral ischemia per se did not affect the concentrations of nicotinamide and NAD+ both in the penumbra and ischemic core. In the nicotinamide groups, the brain nicotinamide levels increased significantly in all areas examined, and brain NAD+ levels increased in the penumbra but not in the ischemic core. Increased brain levels of nicotinamide are considered to be primarily important for neuroprotection against ischemia, and the protective action may be partly mediated through the increased NAD+ in the penumbra.
 ...
PMID:Nicotinamide attenuates focal ischemic brain injury in rats: with special reference to changes in nicotinamide and NAD+ levels in ischemic core and penumbra. 1283 63

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
 ...
PMID:Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. 1283 3

The glycine site, N-methyl-D-aspartate antagonist 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA1021) was previously tested only in models of transient stroke with pre-treatment paradigms. We therefore tested whether it would protect in two models of permanent stroke in two rat strains with delayed treatment. Intravenous ACEA1021 reduced cerebral infarction by 62% (15 min treatment delay) and 42% (2 h treatment delay), relative to vehicle-injected rats, when subjected to a modified Tamura and permanent intraluminal filament model of stroke, respectively. In comparison, intravenous nicotinamide (500 mg/kg), which was tested in separate animal cohorts, had no significant effect on infarction. These data show that ACEA1021 protects against permanent focal cerebral ischemia, even with a 2 h post-treatment delay. Characterization of the therapeutic window with longer outcome times including infarction and neurobehavioral endpoints is needed.
 ...
PMID:Delayed treatment with 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, a glycine site N-methyl-D-aspartate antagonist, protects against permanent middle cerebral artery occlusion in male rats. 1287 7

The purpose of the current study was to investigate aspects of improved bioenergetic function using nicotinamide during stroke. Using a global ischemia-reperfusion mouse model, ATP was depleted by 50% in the brain. The use of nicotinamide to provide a large reserve of brain NAD+ restored ATP levels to 61% of control levels. Alternatively, using nicotinamide as a PARP inhibitor restored ATP levels up to 72%. However, using a large reserve of NAD+ in the brain together with PARP inhibition proved to be additive, restoring ATP to 85% of control levels during the first critical 5 min of reperfusion. NAD+ and ATP levels correlated almost exactly. Brain mitochondrial function was also examined after cerebral ischemia-reperfusion. State 3 respiration of complex I was found to be abolished. However, this was a non-permanent inhibition of activity in vitro, since (NADH ubiquinone oxideroductase) complex I activity in these mitochondria was restored upon the addition of NADH. In vivo, the use of increased brain NAD+ and PARP inhibition was able to partially restore mitochondrial respiration. Taken together, the results show that nicotinamide offers a substantial protective role in terms of preservation of cellular ATP and mitochondrial NAD-linked respiration.
 ...
PMID:Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. 1451 2


<< Previous 1 2 3 4 5 6 7 Next >>