Neuronal expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) and 15d-prostaglandin J2--mediated protection of brain after experimental cerebral ischemia in rat.

Existing experimental evidence suggests that PPARgamma may play a beneficial role in neuroprotection from various brain pathologies. Here we found that focal cerebral ischemia induced by middle cerebral/common carotid arteries occlusion (MCA/CCAo) induced up-regulation of PPARgamma messenger RNA in the ischemic hemisphere as early as 6 h after the ischemic event. The increased PPARgamma mRNA expression was primarily associated with neurons in the ischemic penumbra, suggesting an important role for PPARgamma in neurons after ischemia. Intraventricular injection of 15d-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a proposed endogenous PPARgamma agonist, into the ischemic rat brains significantly increased the PPARgamma-DNA-binding activity and reduced infarction volume at 24 h after reperfusion. We propose that PPARgamma up-regulation in response to ischemia may contribute to PPARgamma activation in the presence of PPARgamma agonists. Activation of PPARgamma in neurons at an early stage after ischemia may represent a pro-survival mechanism against ischemic injury.

Ischemic stunning of the brain: early recanalization without immediate clinical improvement in acute ischemic stroke.

BACKGROUND AND PURPOSE: Early arterial recanalization (ER) with intravenous tissue plasminogen activator (tPA) can lead to dramatic clinical recovery, whereas some patients do not experience immediate clinical improvement. METHODS: Consecutive patients received tPA 0.9 mg/kg IV within 3 hours after symptom onset. All had M1 or M2 middle cerebral artery occlusions on pretreatment transcranial Doppler. Patients were continuously monitored for 2 hours after bolus. ER was defined as the Thrombolysis in Brain Ischemia intracranial flow increase by >or=1 grade. Stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and recovery (modified Rankin Scale) were assessed independently of transcranial Doppler. RESULTS: One hundred twenty patients (mean age, 68+/-15 years; 63 women; median NIHSS, 17; range, 5 to 29; 90% with >or=10 points) received tPA at a median of 120 minutes, 50% within the first 2 hours. ER was observed in 73 patients (32 complete, 41 partial). No immediate clinical changes (n=23) or worsening (by 1 to 6 points on NIHSS, n=4) was observed in 37% of ERs (nonresponders). Complete ER was found in 8 of these 27 patients. At 24 hours, 22 of 27 patients (82%) had persisting deficits of NIHSS >or=10 points, yet 37% of these nonresponders (10 of 27) still achieved good outcome (modified Rankin score, 0 to 2) at 3 months. Among nonresponders with good outcome, 100% had detectable residual flow signals, and 70% had compensatory flow diversion on prebolus transcranial Doppler compared with 65% and 29% of nonresponders with poor outcome (P<0.05). Compared with responders (n=46), nonresponders had similar prebolus median NIHSS of 16 to 17 points, bolus times of 120 to 132 minutes, median speed of thrombolysis (30 minutes), and ER times of 190 to 193 minutes after onset. Reocclusion occurred in 3 of 4 patients with clinical worsening, 30% of other nonresponders, and 22% of responders. Symptomatic hemorrhage rate was 4% in both groups. At 3 months, mortality was 33% in nonresponders compared with 9% in responders (P=0.001). CONCLUSIONS: After successful arterial ER with tPA therapy, lack of early clinical changes or worsening is relatively common (37%) and appears to be independent of time to tPA bolus or reperfusion. However, with tPA alone, at least one third of these nonresponders still achieved good outcomes at 3 months, suggesting the possibility of a "stunned brain" syndrome with delayed recovery. Several different mechanisms may potentially account for this phenomenon.

Clinical trials for cytoprotection in stroke.

To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-to-treat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke.

BACKGROUND AND PURPOSE: In animal models, the combination of caffeine and ethanol (caffeinol) provides robust neuroprotection at blood levels that should be easily and safely achieved in humans. This study was designed to determine the safety and tolerability of ascending doses of this combination in stroke patients. METHODS: This Food and Drug Administration-approved open-label, single-arm, dose-escalation study had 3 original dose groups: group 1, caffeine 6 mg/kg plus ethanol 0.2 g/kg; groups 2 and 3, incremental increases of caffeine and ethanol by 2 mg/kg and 0.2 g/kg, respectively. Intravenous thrombolysis was encouraged if patients qualified. Drug was started within 6 hours of stroke onset, and blood levels of caffeine and ethanol were drawn at baseline and end of infusion. The target blood caffeine and ethanol ranges were 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. Clinical outcome measurements included the National Institutes of Health Stroke Scale at the end of infusion, at 24 hours, and at discharge. Potential complications from caffeine and ethanol were recorded. Cases were reviewed by an independent stroke neurologist for safety. RESULTS: A total of 23 patients were recruited. Target blood caffeine and ethanol levels were reached in 0 of the 4 patients in the first group. The second dose group (caffeine 8 mg/kg plus ethanol 0.4 g/kg) included 8 patients. The median end-of-infusion caffeine and ethanol levels were within the desired target ranges. Two days after infusion, 1 patient in this group with preexisting cardiac disease and end-of-infusion caffeine and ethanol levels of 10.7 microg/mL and 69 mg/dL developed reversible congestive heart failure and required transfer to an intensive care unit. The original third dose group was canceled given achievement of target blood caffeine and ethanol levels in group 2. However, 3 new dose groups were created in an attempt to minimize the dose of ethanol. Although blood levels were proportional to dose, none of these new dose groups provided optimal blood levels. Congestive heart failure occurred in 1 other patient with previously asymptomatic cardiomyopathy. No other side effects were noted. Concomitant thrombolytic therapy was given in 8 patients, 1 of whom died of intracerebral hemorrhage. CONCLUSIONS: Caffeinol alone or combined with intravenous tissue plasminogen activator can be administered safely. Caffeine 8 mg/kg plus ethanol 0.4 g/kg produces target caffeine and ethanol levels of 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. A randomized, placebo-controlled trial is needed to determine the neuroprotective effect of this combination.

Perspectives on reperfusion-induced damage in rodent models of experimental focal ischemia and role of gamma-protein kinase C.

Ischemic stroke represents the leading cause of death and disability among elderly people. Most stroke survivors are left with lifelong disability. With the exception of tissue-type plasminogen activator (t-PA), no effective therapy exists for the management of acute stroke. Understanding the role of various extrinsic and intrinsic pathogenic factors of ischemic damage represents a prime objective of ongoing stroke research. An important variable affecting stroke outcome is the presence or absence of reperfusion (recanalization of the occluded vessel) following an ischemic event. It appears that early reperfusion after a stroke is beneficial and capable of reversing the majority of ischemic dysfunctions. However, in some instances, late reperfusion may contrarily trigger deleterious processes and lead to more ischemic damage. Examples of ischemia/reperfusion damage using an experimental model of focal ischemia in rodents are provided, along with evidence that the brain-enriched gamma-isoform of protein kinase C may represent an important mediator of reperfusion-induced brain injury in mutant mice.

Is the benefit of early recanalization sustained at 3 months? A prospective cohort study.

BACKGROUND AND PURPOSE: Early arterial recanalization can lead to dramatic recovery (DR) during intravenous tissue plasminogen activator (tPA) therapy. However, it remains unclear whether this clinical recovery is sustained 3 months after stroke. METHODS: We studied consecutive patients treated with intravenous tPA (0.9 mg/kg within 3 hours) who had M1 or proximal M2 middle cerebral artery occlusion on pretreatment transcranial Doppler according to previously validated criteria. Patients were continuously monitored for 2 hours after tPA bolus to determine complete, partial, or no early recanalization with the Thrombolysis in Brain Ischemia (TIBI) flow grading system. A neurologist obtained the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores independently of transcranial Doppler results. DR was defined as a total NIHSS score of 0 to 3 points, and early recovery (ER) was defined improvement by > or =10 points at 2 hours after tPA bolus. Good long-term outcome was defined as an NIHSS score of 0 to 2 or an mRS score of 0 to 1 at 3 months. RESULTS: Fifty-four patients with proximal middle cerebral artery occlusion had a median prebolus NIHSS score of 16 (range, 6 to 28; 90% with > or =10 points). The tPA bolus was given at 130+/-32 minutes (median, 120 minutes; 57% treated within the first 2 hours). DR+ER was observed in 50% of patients with early complete recanalization (n=18), 17% with partial recanalization (n=18), and 0% with no early recanalization (n=18) (P=0.025). Overall, DR+ER was observed in 12 patients (22%), and 9 (75%) had good outcome at 3 months in terms of NIHSS (P=0.009) and mRS (P=0.006) scores compared with non-DR and non-ER patients. If early recanalization was complete, 50% of these patients had good outcome at 3 months, and 78% with DR+ER sustained early clinical benefit. If recanalization was partial, 44% had good long-term outcome, and 66% of patients with DR+ER sustained the benefit. If no early recanalization occurred, 22% had good long-term outcome despite the lack of DR within 2 hours of tPA bolus (P=0.046). Mortality was 11%, 11%, and 39% in patients with complete, partial, and no early recanalization, respectively (P=0.025). Reasons for not sustaining DR in patients with early recanalization were subsequent symptomatic intracranial hemorrhage and recurrent ischemic stroke. CONCLUSIONS: DR or ER after recanalization within 2 hours after tPA bolus was sustained at 3 months in most patients (75%) in our study. Complete or partial early recanalization leads to better outcome at 3 months after stroke. Fewer patients achieve good long-term outcome without early recanalization.

Residual flow signals predict complete recanalization in stroke patients treated with TPA.

BACKGROUND: Residual blood flow around thrombus prior to treatment predicts success of coronary thrombolysis. The authors aimed to correlate the presence of residual flow signals in the middle cerebral artery (MCA) with completeness of recanalization after intravenous tissue plasminogen activator (TPA). METHODS: The authors studied consecutive patients treated with intravenous TPA therapy who had a proximal MCA occlusion on pretreatment transcranial Doppler (TCD). Patients were continuously monitored for 2 hours after TPA bolus. Absent residual flow signals correspond to the thrombolysis in brain ischemia (TIBI) 0 grade, and the presence of residual flow signals was determined as TIBI 1-3 flow grades. Complete recanalization was defined as flow improvement to TIBI grades 4-5. RESULTS: Seventy-five patients with a proximal MCA occlusion had median pre-bolus NIHSS 16 (85% with > or = 10 points). TPA bolus was given at 141 +/- 56 minutes (median 120 minutes). Complete recanalization was observed in 25 (33%), partial in 23 (31%), and no early recanalization was seen in 27 (36%) patients within 2 hours after TPA bolus. Only 19% with absent residual flow signals (TIBI grade 0, n = 26) on pretreatment TCD had complete early recanalization. If pretreatment TCD showed the presence of any residual flow (TIBI 1-3, n = 49), 41% had complete recanalization within 2 hours of TPA bolus (P = .03). CONCLUSIONS: Patients with detectable residual flow signals before IV TPA bolus are twice as likely to have early complete recanalization. Those with no detectable residual flow signals have less than 20% chance for complete early recanalization with intravenous TPA and may be candidates for intra-arterial therapies.

Sex and acute stroke presentation.

STUDY OBJECTIVES: We determine whether a sex difference exists for acute stroke emergency department presentation. METHODS: The TLL Temple Foundation Stroke Project is a prospective observational study of acute stroke management that identified 1,189 validated strokes in nonurban community EDs from February 1998 to March 2000. Structured interview of the patient and the person with the patient at symptom onset identified the symptom or symptoms that prompted the patient to seek medical attention. Interview data were available for 1,124 (94%) patients. A physician blinded to sex classified the reported symptoms into 14 categories. RESULTS: Nontraditional stroke symptoms were reported by 28% of women and 19% of men (odds ratio 1.62; 95% confidence interval 1.2 to 2.2). Nontraditional stroke symptoms, pain (men 8%, women 12%) and change in level of consciousness (men 12%, women 17%), were more often reported by women. Traditional stroke symptoms, imbalance (men 20%, women 15%) and hemiparesis (men 24%, women 19%), were reported more frequently by men. Trends were also found for women to present with nonneurologic symptoms (men 17%, women 21%) and men to present with gait abnormalities (men 11%, women 8%). There was no sex difference in the mean number of symptoms reported by an individual patient. CONCLUSION: This study suggests that a sex difference exists in reporting of acute stroke symptoms. Women with validated strokes present more frequently with nontraditional stroke symptoms than men. Recognition of this difference might yield faster evaluation and management of female patients with acute stroke eligible for acute therapies.