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Piyush M Patel

Publications and source records attributed to Piyush M Patel.

8 recordsLinked to original sources
PubMed2006

Reevaluation of gray and white matter injury after spinal cord ischemia in rabbits.

BACKGROUND: Although gray matter injury has been well characterized, the available data on white matter injury after spinal cord ischemia (SCI) in rabbits are limited. The current study was conducted to investigate the evolution of ischemia induced injury to gray and white matter and to correlate this damage to hind-limb motor function in rabbits subjected to SCI. METHODS: Thirty-eight rabbits were randomly assigned to 24-h, 4-day, or 14-day reperfusion groups or a sham group (n = 9 or 10 per group). SCI was induced by occlusion of the infrarenal aorta for 16 min. Hind-limb motor function was assessed using the Tarlov scale (0 = paraplegia, 4 = normal). The gray matter damage was assessed on the basis of the number of normal neurons in the anterior spinal cord. White matter damage was assessed on the basis of the extent of vacuolation and accumulation of amyloid precursor protein immunoreactivity. RESULTS: Tarlov scores gradually decreased and reached a nadir 14 days after reperfusion. There were no significant differences in the number of normal neurons among the 24-h, 4-day, and 14-day groups. The extent of vacuolation, expressed as a percent of total white matter area, was significantly greater in the 4-day and 14-day groups in comparison with the sham group. By contrast, there was no difference in vacuolation between the sham and 24-h groups. Amyloid precursor protein immunoreactivity was greater in the 4-day and 14-day groups. CONCLUSION: The results in the current study show that SCI induced white matter injury as well as gray matter injury in a rabbit model of SCI. The time course for 14 days after reperfusion may differ among the gray and white matter damages and hind-limb motor function in rabbits subjected to SCI.

Amyloid beta-Protein Precursor↗
PubMed2006

The combination of isoflurane and caspase 8 inhibition results in sustained neuroprotection in rats subject to focal cerebral ischemia.

Although isoflurane can reduce ischemic neuronal injury after short postischemic recovery intervals, data from our laboratory have demonstrated that this neuroprotection is not sustained and that delayed apoptotic neuronal death, mediated in part by activation of caspases, contributes to the gradual increase in the size of the infarction. We tested the hypothesis that the neuroprotective efficacy of isoflurane can be prolonged with the administration of z-IETD-fmk, a specific inhibitor of caspase 8. Fasted Wister rats were anesthetized with isoflurane and randomly allocated to awake-vehicle, isoflurane-vehicle, awake-IETD, or isoflurane-IETD groups (n = 25 per group). Animals were subjected to 60 min focal ischemia by filament occlusion of the middle cerebral artery (MCAO). Daily intracerebroventricular injections of z-IETD-fmk or vehicle were administered via an implanted cannula starting before ischemia and continuing until 14 days post-MCAO. Neurological assessment was performed 14 days after ischemia after which the volume of cerebral infarction and number of intact neurons in the peri-infarct cortex were determined. Total infarction volume was less in the isoflurane-IETD group than in awake-vehicle, isoflurane-vehicle, and awake-IETD groups. Infarction volume was also less in the awake-IETD group versus the awake-vehicle group. The number of intact neurons within the peri-infarct cortex was significantly less in the awake-vehicle group in comparison with the other three experimental groups. The isoflurane-IETD group had better neurologic outcomes than both vehicle-treated groups at 14 days post-MCAO. These results suggest that a combination of isoflurane and a caspase 8 inhibitor can produce neuroprotection that is evident even after a recovery period of 14 days. This combination demonstrated greater efficacy than the administration of either isoflurane or z-IETD-fmk alone. These results are consistent with the premise that continuing apoptosis contributes to the enlargement of cerebral infarction during the recovery period and that its inhibition can provide sustained neuroprotection.

Animals↗
PubMed2005

Neuroprotective effects of anesthetic agents.

Ischemic neuronal injury is characterized by early death mediated by excitotoxicity and by delayed death caused by apoptosis. Current evidence indicates that volatile agents, barbiturates, and propofol can protect neurons against ischemic injury caused by excitotoxicity. In the case of volatile agents and propofol, neuroprotection may be sustained if the ischemic insult is relatively mild; however, with moderate to severe insults, this neuronal protection is not sustained after a prolonged recovery period. This suggests that volatile agents and propofol do not reduce delayed neuronal death caused by apoptosis. The long-term effects of barbiturates on ischemic cerebral injury are not yet defined. Cerebral ischemia is characterized by continued neuronal loss for a long time after the initial ischemic insult. Therefore, in investigations of cerebral ischemia, the duration of the recovery period should be taken into consideration in the analysis of the neuroprotective effects of anesthetic agents. A combination of different approaches that target specific stages of the evolution of ischemic injury may be required for sustained neuroprotection.

Anesthetics↗
PubMed2005

The role of nitric oxide synthase inhibition in the adverse effects of etomidate in the setting of focal cerebral ischemia in rats.

We evaluated the effect of N(G)-nitro-L-arginine-methyl-ester (l-NAME, a nitric oxide synthase [NOS] inhibitor) and L-arginine (nitric oxide substrate) on cerebral mitochondrial dysfunction (hereafter referred to as "injury") after temporary middle cerebral artery occlusion (MCAo) during halothane or etomidate anesthesia in spontaneously hypertensive rats. Sixty minutes before MCAo, rats were randomized to 1 of 5 regimens (n = 8 per group): h/control, 1.2 minimum alveolar anesthetic concentration of halothane; h/L-NAME, 1.2 minimum alveolar anesthetic concentration of halothane and L-NAME (30 mg/kg); etomidate, an electroencephalographic (EEG) burst suppression dose of etomidate; e/L-NAME, an EEG burst suppression dose of etomidate and L-NAME (30 mg/kg); or e/L-NAME/arg, an EEG burst suppression dose of etomidate, L-NAME (30 mg/kg), and L-arginine (bolus of 300 mg/kg with an infusion at 35 mg x kg(-1) x min(-1)). After 180 min of MCAo and 120 min of reperfusion, volume of injury was determined using 2,3,5-triphenytetrazolium stain. Injury volume (mm(3), mean +/- sd) was larger in the etomidate group (153 +/- 17) than the halothane anesthetized h/control group (93 +/- 16) (P < 0.05) but did not differ between the e/L-NAME (162 +/- 17) and h/L-NAME groups (155 +/- 26). Injury volume in the e/L-NAME/arg group (88 +/- 15) was not different from the h/control group (93 +/- 16) and was less than that in either the etomidate or the e/L-NAME groups (P < 0.05). The data reproduce our previous observation that, relative to a halothane-anesthetized control state, etomidate has an adverse effect on ischemic injury in the setting of temporary focal cerebral ischemia. Prior inhibition of NOS with L-NAME resulted in no difference in the volume of injury between groups receiving etomidate or halothane (162 +/- 17 versus 155 +/- 26). Administration of a large dose of L-arginine prevented the adverse effect of etomidate. The data were obtained after only 2 h of reperfusion and therefore cannot be construed as representative of final neurologic outcome. They nonetheless suggest that etomidate produces an adverse effect on mitochondrial function early in the course of focal cerebral ischemia, in part, by inhibition of NOS.

Animals↗
PubMed2004

Combination of isoflurane and caspase inhibition reduces cerebral injury in rats subjected to focal cerebral ischemia.

BACKGROUND: Recent data indicate that the neuroprotective efficacy of isoflurane is not sustained. Delayed neuronal death, mediated in part by apoptosis, contributes to the gradual increase in the size of the infarction. These data suggest that isoflurane may not be able to inhibit delayed neuronal death. The prevention of apoptosis by a caspase inhibitor might provide neuroprotection in addition to that provided by isoflurane. The current study was conducted to determine whether isoflurane-mediated neuroprotection can be made more durable with the administration of z-VAD-fmk, a nonspecific caspase inhibitor. METHODS: Fasted Wister rats were allocated to awake-zVAD, awake-vehicle, isoflurane-zVAD, or isoflurane-vehicle groups (n = 16/group). Animals were subjected to focal ischemia for 60 min by filament occlusion of the middle cerebral artery. In the awake groups, isoflurane was discontinued after occlusion of the middle cerebral artery. In the isoflurane groups, isoflurane anesthesia was maintained at 1.5 minimum alveolar concentration during occlusion of the middle cerebral artery. Before and after ischemia, daily injections of z-VAD-fmk or vehicle were administered into the lateral cerebral ventricle for 14 days. Neurologic assessment was performed 14 days after ischemia. The volume of cerebral infarction and the number of intact neurons in the periinfarct cortex were determined by image analysis of hematoxylin and eosin-stained coronal brain sections. RESULTS: Infarction volume was less in the isoflurane-zVAD group (23 +/- 11 mm, mean +/- SD) than in isoflurane-vehicle, awake-vehicle, and awake-zVAD groups (82 +/- 31, 86 +/- 31, and 59 +/- 25 mm, respectively; P < 0.05). In comparison with the awake-vehicle and isoflurane-vehicle groups, the administration of z-VAD-fmk significantly decreased infarction volume (P < 0.05). The infarction volume between the awake-vehicle and isoflurane-vehicle groups was not different. The number of intact neurons within the periinfarct cortex was significantly less in the awake-vehicle group than in the other three groups (P < 0.05). The isoflurane-zVAD group demonstrated better neurologic function than the awake-vehicle group (P < 0.05). CONCLUSION: These findings are consistent with the premise that ongoing delayed neuronal death, in part mediated by apoptosis, contributes to the progression of cerebral infarction during the recovery period, and its inhibition can provide sustained neuroprotection.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Effect of isoflurane on neuronal apoptosis in rats subjected to focal cerebral ischemia.

UNLABELLED: Although isoflurane can reduce ischemic neuronal injury after short postischemic recovery intervals, this neuroprotective efficacy is not sustained. Neuronal apoptosis can contribute to the gradual increase in infarct size after ischemia. This suggests that isoflurane, although capable of reducing early neuronal death, may not inhibit ischemia-induced apoptosis. We investigated the effects of isoflurane on markers of apoptosis in rats subjected to focal ischemia. Fasted Wistar-Kyoto rats were anesthetized with isoflurane and randomly allocated to awake (n = 40) or isoflurane (n = 40) groups. Animals in both groups were subjected to focal ischemia by filament occlusion of the middle cerebral artery for 70 min. Pericranial temperature was servo-controlled at 37 degrees C +/- 0.2 degrees C throughout the experiment. In the awake group, isoflurane was discontinued and the animals were allowed to awaken. In the isoflurane group, isoflurane anesthesia was maintained at 1.5 MAC (minimum alveolar anesthetic concentration). Animals were killed 7 h, 1 day, 4 days, or 7 days after reperfusion (n = 10/group/time point). The area of cerebral infarction was measured by image analysis in a hematoxylin and eosin stained section. In three adjacent sections, apoptotic neurons were identified by TUNEL staining and immunostaining for active caspase-9 and caspase-3. Infarct size was smaller in the isoflurane group than the awake group 7 h, 1 day, and 4 days after reperfusion (P < 0.05). However, this difference was absent 7 days after reperfusion. The number of apoptotic (TUNEL, caspase-3, and caspase-9 positive) cells 1 day after ischemia was significantly more in the awake versus isoflurane group. After a recovery period of 4 or 7 days, the number of apoptotic cells in the isoflurane group was more than in the awake group. After 7 days, the number of caspase-3 and -9 positive neurons was more in the isoflurane group (P < 0.05). The data indicate that isoflurane delays but does not prevent the development of cerebral infarction caused by ischemia. Isoflurane reduced the development of apoptosis early after ischemia but did not prevent it at later stages of postischemic recovery. IMPLICATIONS: The effect of isoflurane on neuronal apoptosis was investigated in rats subjected to focal cerebral ischemia. In isoflurane-anesthetized animals, ischemia-induced apoptosis occurred during the later stages of postischemic recovery. Isoflurane did not inhibit postischemic neuronal apoptosis.

Anesthetics, Inhalation↗
PubMed2003

Ischemic preconditioning in the brain.

PURPOSE OF REVIEW: Brain ischemia is responsible for significant morbidity and mortality associated with cardiovascular surgery, and is the end result of multiple disease states, including cardiac arrest, stroke, and traumatic brain injury. Despite significant resources dedicated to developing neuroprotective strategies, little progress has been made in this regard. Neuronal ischemic preconditioning is an endogenous neuroprotective strategy that provides sustained and robust ischemic tolerance. Identification of the mechanisms responsible for mediating the preconditioning response may offer novel therapeutic targets and further our understanding of the natural adaptations to brain injury. RECENT FINDINGS: Recent research efforts have elucidated many intracellular signaling pathways that ultimately lead to ischemic tolerance after a preconditioning stimulus. Most of these are associated with glutamate receptor signal transduction, the intracellular kinases, and several transcription regulators. Microarray analysis has identified several gene families that warrant further investigation to identify novel candidates for neuroprotective therapies. These include genes involved in synaptic architecture and signal propagation, cell cycle and transcription regulators, and mediators of apoptosis such as the heat shock proteins and anti-apoptotic mitochondrial proteins. SUMMARY: Neuronal ischemic preconditioning is an endogenous mechanism that leads to robust neuroprotection from ischemia. Identification of the upstream pathways that initiate preconditioning and candidate genes that mediate this phenomenon may offer novel therapeutic targets, with applicability to a variety of disease states and perioperative complications.

Journal Article↗