Comparison between moyamoya disease and moyamoya syndrome in Israel.

BACKGROUND AND AIMS: Moyamoya is a chronic brain vasculopathy involving the distal intracranial internal carotid artery (ICA) or proximal middle cerebral artery (MCA). Moyamoya patients can be divided into those with primary moyamoya disease (MMD) and those with moyamoya secondary to other known causes such as intracranial atherosclerosis (moymoya syndrome [MMS]). Our aim was to compare the characteristics of MMD patients to those of MMS patients in a sample of Israeli patients seen over the course of 20 years at a tertiary referral center. METHODS: Included patients were diagnosed with either MMD or MMS based on typical imaging findings and the presence or absence of known concomitant vascular risk factors or associated disorders and vascular disease. Patients with MMS were compared to those with MMD. Demographics, symptoms, signs, and radiological data were compared between the groups. Treatment options and long-term rates of recurrent stroke and functional outcome were also studied. RESULTS: Overall, 64 patients were included (25 MMD, 39 MMS). Patients with MMD were significantly younger (median IQR 20 (7-32) vs. 40 (19-52); p=0.035). Patients with MMS more often had vascular risk factors but there were no significant differences in clinical presentations or long-term disability rates between the groups and a similar proportion of patients underwent surgical interventions to restore hemispheric perfusion in both groups (48% vs. 44% MMS vs. MMD; p=0.7). Almost one in four patient had a recurrent stroke after the initial diagnosis in both groups. Most recurrences occurred in the pre-surgery period in the MMS group and in the post-surgery period in the MMD group. CONCLUSIONS: There were no statistically significant differences in clinical or radiological presentations between the MMS and MMD patients. The course is not benign with recurrent stroke occurring in as many as 25%. More data is needed in order to identify those at high risk for stroke occurrence and recurrence.

Covid-19 associated free hanging clots in acute symptomatic carotid stenosis.

BACKGROUND: Thrombotic complications including stroke were previously described following Covid-19. We aim to describe the clinical and radiological characteristics of Covid-19 related with acutely symptomatic carotid stenosis (aSCS). METHOD: All patients presenting with an aSCS were prospectively enrolled in an ongoing institutional database. Inclusion criteria for the Covid-19-aSCS group were a combination of both antigen test and a positive reverse-transcriptase (PCR) test for Covid-19 upon admission. Patients with additional potential etiologies for stroke including cardioembolism, carotid dissection or patients with stenosis of <50% on CTA were excluded. A cohort of non-Covid-19 related aSCS patients admitted to the same institution before the pandemic during 2019 served as controls. RESULTS: Compared to controls (n = 31), Covid-19-aSCS (n = 8), were younger (64.2 ± 10.7 vs 73.5 ± 10, p = 0.027), and less frequently had hypertension (50% vs 90%, p = 0.008) or hyperlipidemia (38% vs 77%, p = 0.029) before admission. Covid-19-aSCS patients had a higher admission NIHSS score (mean 9 ± 7 vs 3 ± 4, p = 0.004) and tended to present more often with stroke (88% vs 55%, p = 0.09) rather than a TIA. Covid-19-aSCS patients had higher rates of free-floating thrombus and clot burden on CTA (88% vs 6.5%, p = 0.002). Covid-19 patients also less often achieved excellent outcomes, with lower percentage of mRS score of 0 after 90-days (13% vs 58%, p = 0.022). CONCLUSION: Covid-19- aSCS may occur in a younger and healthier subpopulation. Covid-19- aSCS patients may have higher tendencies for developing complex clots and less often achieve excellent outcomes.

Predictors and Prognostic Implications of Hemorrhagic Transformation Following Cerebral Endovascular Thrombectomy in Acute Ischemic Stroke: A Multicenter Analysis.

PURPOSE: Hemorrhagic transformation (HT) following cerebral endovascular thrombectomy (EVT) for large vessel occlusion (LVO) in acute ischemic stroke is associated with poor outcome. Recent studies have shown that EVT can be efficacious in imaging-selected patients as late as 6-24 h from onset (late time window; LTW). We sought to determine predictors and prognostic implications of HT following EVT in LTW. METHODS: Consecutive patients undergoing EVT for LVO were recruited into a prospective multicenter database. HT was divided into petechial hemorrhagic-infarction and parenchymal hematoma (PH) type 1 or 2 defined as confluent hemorrhage covering < or > than 1/3 of the infarct volume, respectively. Multivariate analyses were performed to determine variables associated with HT subtypes. RESULTS: Among 611 patients included (mean age 70.5 ± 12.5 years; median NIHSS 16), 115 (18.8%) had HT and 33 of them (5.4%) had PH2. Independent PH2 predictors included failed recanalization (OR 7.0, 95% CI 2.3-21.6), longer time from symptom onset to admission (OR 1.002 per minute 95% CI 1.001-1.003) and hyperlipidemia (OR 3.12; 95%CI 1.12-8.7). HT was not associated with outcome. In contrast, PH2 patients had lower favorable outcome rates (14.3 vs 41.6%, p = 0.004) and higher mortality rates (39 vs 17%, p = 0.001). Patients who underwent EVT in the late versus early window had similar PH2 rates (4.5 vs 6.7%, p = 0.27). In multivariate models, PH2 tripled the odds of both 90-day poor outcome (OR 3.1, 95% CI 1.01-9.5) and 90-day mortality (OR 3.2, 95% CI 1.4-7.3). CONCLUSIONS: PH2 following EVT is associated with increased mortality and unfavorable outcome rates. Rates of PH2 are not different between LTW patients and those treated < 6 h from symptom onset.

Outcomes after reperfusion therapies in patients with ACA stroke: A multicenter cohort study from the EVATRISP collaboration.

BACKGROUND: Patients with stroke secondary to occlusions of the anterior cerebral artery (ACA) often have poor outcomes. The optimal acute therapeutic intervention for these patients remains unknown. METHODS: Patients with isolated ACA-stroke were identified from 10 centers participating in the EndoVascular treatment And ThRombolysis in Ischemic Stroke Patients (EVATRISP) prospective registry. Patients treated with endovascular thrombectomy (EVT) were compared to those treated with intravenous thrombolysis (IVT). Odds ratios with 95% confidence intervals (OR; 95%CI) were calculated using multivariate regression analysis. RESULTS: Included were 92 patients with ACA-stroke. Of the 92 ACA patients, 55 (60%) were treated with IVT only and 37 (40%) with EVT (±bridging IVT). ACA patients treated with EVT had more often wake-up stroke (24% vs. 6%, p = 0.044) and proximal ACA occlusions (43% vs. 24%, p = 0.047) and tended to have higher stroke severity on admission [NIHSS: 10.0 vs 7.0, p = 0.054). However, odds for favorable outcome, mortality or symptomatic intracranial hemorrhage did not differ significantly between both groups. Exploration of the effect of clot location inside the ACA showed that in patients with A1 or A2/A3 ACA occlusions the chances of favorable outcome were not influenced by treatment allocation to IVT or EVT. DISCUSSION: Treatment with either IVT or EVT could be safe with similar effect in patients with ACA-strokes and these effects may be independent of clot location within the occluded ACA.

Clopidogrel underactivity is a common in patients with acute symptomatic severe carotid stenosis.

BACKGROUND: Clopidogrel is commonly used for secondary stroke prevention in patients with large vessel stenosis. Reduced Clopidogrel high on treatment platelet reactivity (CR) can lead to Clopidogrel underactivity (CU) causing acute thrombosis. However, the prevalence of CU among patients with acute symptomatic carotid disease remains unknown. Therefore, we aimed to find the prevalence and identify the predictors for CU among patients with acutely symptomatic carotid stenosis. PATIENTS AND METHODS: Over the span of 14 months, CR was measured at the time of endovascular procedure in all patients undergoing angiography and stenting because of acute symptomatic carotid stenosis. Only patients treated per institutional protocol with a combination of Clopidogrel and Aspirin were included. CR was measured with VerifyNowP2Y12 reaction units (PRU) and CU was defined as PRU > 208. Patients with CU were compared to those without CU. RESULTS: Thirty-five patients were included (mean age 71.3 ± 10, 76% men) and twelve (34.3%, mean age 71.8 ± 8.4, 58% men) had CU at the time of endovascular intervention. On univariate analysis more severe carotid stenosis was seen in CU patients (92.6 ± 6.5% vs 81.6 ± 13.6%, p = 0.013) and percent stenosis was independently associated with CU on multivariate analysis (p = 0.023). CONCLUSIONS: CU is present in 1 of every 3 patients with acutely symptomatic carotid disease. The current results suggest that CR testing should become part of routine care in patients with acutely symptomatic carotid disease.

Influence of atrial fibrillation detection time on outcome after endovascular thrombectomy.

BACKGROUND: Cardiac emboli secondary to atrial fibrillation (AF) commonly cause large vessel occlusions (LVO) that require endovascular thrombectomy (EVT) to restore cerebral circulation. Whether the outcome of patients with AF diagnosed after the index stroke (newAF) differs from that of AF-patients in which AF was known before stroke (kAF) remains unknown. PATIENTS AND METHODS: Consecutive LVO patients treated with EVT were recruited and the data was analyzed retrospectively. We compared patients with newAF to those with kAF and those without AF. RESULTS: Among 230 patients included, 109 (47%) had AF (86 kAF, 23 newAF). Patients with kAF more often had prior strokes compared with those with newAF (20% vs. 4% p = 0.04) but other parameters did not differ between the groups. Both AF groups were significantly older, more often reached favorable recanalization and less often had favorable outcomes compared to those without AF. On multivariate analyses, timing of AF detection did not influence survival (Odds Ration [OR] 0.89 95% Confidence Interval [CI] 0.28-1.90), chances for favorable recanalization (OR 1.2 95% CI 0.44-3.26) or favorable outcome 1.32 (95% CI 0.57-3.05). CONCLUSIONS: Timing of AF diagnosis does not appear to influence outcome in patients with LVO that underwent EVT.

Atrial Fibrillation Treatment Adequacy and Outcome after Endovascular Thrombectomy.

BACKGROUND: Atrial fibrillation (AF) often leads to large vessel occlusions (LVO) which may necessitate endovascular thrombectomy (EVT). Whether the adequacy of treatment with oral anticoagulants (OAC) prior to LVO modifies outcomes remains unknown. PATIENTS AND METHODS: Consecutive EVT-treated LVO patients were recruited and the data was analyzed retrospectively. We combined patients with known AF that were untreated with OAC or inadequately treated with those with new-onset AF to form a group of undertreated-AF patients and compared them to adequately treated AF patients. RESULTS: Of the 230 patients included, 109 (47%) had AF (86 known AF, 23 new-onset AF). AF patients were significantly older and more often reached favorable recanalization but less often had favorable outcomes compared to those without AF. Most patients with known AF (76%) were inadequately treated at stroke onset. Patients with undertreated-AF more often received tPA prior to EVT (26% vs. 4% p=0.009), more often had favorable collaterals (65% vs. 33% p<0.001) and more often reached favorable outcomes (28% vs. 9%, p=0.047) compared to adequately treated AF patients. On multivariate analyses adequately treated AF did not impact survival (Odds Ration [OR] 0.89 95% Confidence Interval [CI] 0.23-3.43), chances for favorable recanalization (OR 0.57 95%CI 0.15-2.13) or favorable outcome (OR 5.95 95%CI 0.62-57.39). CONCLUSIONS: Treatment adequacy does not affect the rates of favorable functional outcome or survival in AF patients with LVO.

Intravenous thrombolysis for large vessel or distal occlusions presenting with mild stroke severity.

BACKGROUND AND PURPOSE: We investigated the effectiveness of intravenous thrombolysis (IVT) in acute ischaemic stroke (AIS) patients with large vessel or distal occlusions and mild neurological deficits, defined as National Institutes of Health Stroke Scale scores < 6 points. METHODS: The primary efficacy outcome was 3-month functional independence (FI) [modified Rankin Scale (mRS) scores 0-2] that was compared between patients with and without IVT treatment. Other efficacy outcomes of interest included 3-month favorable functional outcome (mRS scores 0-1) and mRS score distribution at discharge and at 3 months. The safety outcomes comprised all-cause 3-month mortality, symptomatic intracranial hemorrhage (ICH), asymptomatic ICH and severe systemic bleeding. RESULTS: We evaluated 336 AIS patients with large vessel or distal occlusions and mild stroke severity (mean age 63 ± 15 years, 45% women). Patients treated with IVT (n = 162) had higher FI (85.6% vs. 74.8%, P = 0.027) with lower mRS scores at hospital discharge (P = 0.034) compared with the remaining patients. No differences were detected in any of the safety outcomes including symptomatic ICH, asymptomatic ICH, severe systemic bleeding and 3-month mortality. IVT was associated with higher likelihood of 3-month FI [odds ratio (OR), 2.19; 95% confidence intervals (CI), 1.09-4.42], 3-month favorable functional outcome (OR, 1.99; 95% CI, 1.10-3.57), functional improvement at discharge [common OR (per 1-point decrease in mRS score), 2.94; 95% CI, 1.67-5.26)] and at 3 months (common OR, 1.72; 95% CI, 1.06-2.86) on multivariable logistic regression models adjusting for potential confounders, including mechanical thrombectomy. CONCLUSIONS: Intravenous thrombolysis is independently associated with higher odds of improved discharge and 3-month functional outcomes in AIS patients with large vessel or distal occlusions and mild stroke severity. IVT appears not to increase the risk of systemic or symptomatic intracranial bleeding.

Cerebellar hemorrhages in patients with cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) typically involves the cerebral cortex but whether it affects the cerebellum remains uncertain. METHODS: Patients with intracerebral hemorrhage (ICH) who underwent magnetic resonance imaging were prospectively enrolled. Patients were diagnosed with CAA according to the Boston criteria and their hemorrhage types were categorized as macro-hematoma (MH) or microbleeds (MB). Patients with CAA and cerebellar involvement were compared with CAA patients without cerebellar involvement. RESULTS: Out of 614 patients with ICH, 85 (14%) had a post-ICH MRI. Of those, 41 (48%) were diagnosed with possible (n = 19), probable (n = 21) or definite (n = 1) CAA. Cerebellar involvement was seen in 14/41 (34%) patients with CAA. Most cerebellar lesions were of the MB type (35%) and most patients had several cerebellar MB typically involving the cerebellar cortex (85%). Patients with cerebellar involvement had larger numbers of lobar MB but clinical variables including age, gender, risk factor profile, mRS scores at 90 days or survival did not differ between those with and without cerebellar involvement. CONCLUSIONS: Cerebellar involvement may be common in CAA. Most patients have multiple superficial cerebellar MB. Clinical characteristics do not differ between CAA patients with or without cerebellar involvement. Patients presenting with cerebellar ICH should be screened for CAA with MRI.

Clot length does not impact outcome following thrombectomy.

BACKGROUND AND AIMS: Clot length was associated with outcome after treatment with intravenous tissue plasminogen activator (tPA) in patients with stroke secondary to emergent large vessel occlusions (ELVO) but data regarding the influence of clot length on outcome after thrombectomy is lacking. PATIENTS AND METHODS: Prospectively accrued data on consecutive patients with ELVO treated with thrombectomy was analyzed. Data on demographics, risk factors, stroke severity, survival and occurrence of symptomatic intracranial hemorrhage (sICH) was collected. Procedural details including clot length measured on the pre-thrombectomy digital subtraction angiograms in multiple projections were collected. Functional outcome was determined with the modified Rankin Scale (mRS) 90 days post stroke and mRS ≤ 2 was considered as favorable outcome. RESULTS: Data was collected for 94 patients that fulfilled entry criteria. On univariate analysis clot length did not differ between patients with favorable or unfavorable outcomes. Clot length also did not influence the rates of sICH or mortality. On multivariate logistic regression age and stroke severity remained significant modifiers for favorable outcome. In a second regression model age, poor collaterals, the number of passes needed for recanalization and the magnitude of change in neurological deficits between presentation and discharge remained significant modifiers of outcomes. However, clot length had no effect on outcome in both models. CONCLUSIONS: In patients undergoing thrombectomy for ELVO, clot length has no effect on functional outcomes, mortality or sICH. Therefore, patients with ELVO should not be excluded from thrombectomy based on lot length.

Reduced mortality and severe disability rates in the SENTIS trial.

BACKGROUND AND PURPOSE: The Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial showed a trend for reduced all-cause mortality and positive secondary safety end point outcomes. We present further analyses of the mortality and severe disability data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial. MATERIALS AND METHODS: The Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial was a multicenter, randomized, controlled trial that evaluated the safety and effectiveness of the NeuroFlo catheter in patients with stroke. The current analysis was performed on the as-treated population. All-cause and stroke-related mortality rates at 90 days were compared between groups, and logistic regression models were fit to obtain ORs and 95% CIs for the treated versus not-treated groups. We categorized death-associated serious adverse events as neurologic versus non-neurologic events and performed multiple logistic regression analyses. We analyzed severe disability and mortality by outcomes of the mRS. Patient allocation was gathered by use of a poststudy survey. RESULTS: All-cause mortality trended in favor of treated patients (11.5% versus 16.1%; P = .079) and stroke-related mortality was significantly reduced in treated patients (7.5% versus 14.2%; P = .009). Logistic regression analysis for freedom from stroke-related mortality favored treatment (OR, 2.41; 95% CI, 1.22, 4.77; P = .012). Treated patients had numerically fewer neurologic causes of stroke-related deaths (52.9% versus 73.0%; P = .214). Among the 90-day survivors, nominally fewer treated patients were severely disabled (mRS 5) (5.6% versus 7.5%; OR, 1.72; 95% CI, 0.72, 4.14; P = .223). Differences in allocation of care did not account for the reduced mortality rates. CONCLUSIONS: There were consistent reductions in all-cause and stroke-related mortality in the NeuroFlo-treated patients. This reduction in mortality did not result in an increase in severe disability.

Decompressive hemicraniectomy reduces mortality in an animal model of intracerebral hemorrhage.

Decompressive hemicraniectomy (DHC) significantly reduces mortality in patients with large hemispheric ischemic strokes but has not been studied in intracranial hemorrhage (ICH). Male Sabra mice were subjected to large experimental ICH. The animals then underwent DHC or sham surgery. Early (1 day post-op) and late (5 days post-op) mortality rates and neurological disability were monitored. The animals were perfusion-fixed at 5 days post-ICH induction, and their brains were studied for hematoma volume and presence of active caspase 3 as a measure of apoptotic death in the area surrounding the hematoma. Our results show that DHC significantly reduced early (7 vs. 75 %, p < 0.001) and late (46 vs. 83 %, p = 0.017) mortality after large ICH. No significant differences in neurological disability were observed between surviving animals in both groups. Hematoma volumes did not differ between the groups on histological evaluation. The number of active caspase 3-positive neurons at the hematoma boundary was significantly higher in animals that underwent DHC. In conclusion, DHC reduces early and late mortality after devastating ICH without changing the hematoma volumes and without notable effects on motor and sensory functions in survivors. Further evaluation of this method to reduce mortality in ICH patients is warranted.

Delayed leptin administration after stroke induces neurogenesis and angiogenesis.

Leptin is a potent AMP kinase (AMPK) inhibitor that induces neuroprotection, neurogenesis, and angiogenesis when administered immediately after stroke. To dissociate these effects, we explored the effects of delayed administration of leptin, at 10 days after stroke onset, on neurogenesis and angiogenesis after stroke. Sabra mice underwent photothrombotic stroke and were treated with vehicle or leptin given either as a single dose or in triple dosing, 10 days later. Newborn cells were labeled with bromodeoxyuridine. Functional outcome was studied with the neurological severity score for 90 days poststroke, and the brains were then evaluated via immunohistochemistry. Final infarct volumes did not differ between the groups. Exogenous leptin led to significant increments in the number of proliferating BrdU(+) cells in the subventricular zone and in the cortex abutting the lesion (2.5-fold and 1.4-fold, respectively). There were significant increments in the number of newborn neurons and glia (4- and 3.4-fold, respectively) in leptin-treated animals. Leptin also significantly increased the number of blood vessels in the perilesioned cortex. However, animals treated with leptin failed to demonstrate significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis even when given late after stroke but does not lead to better functional outcome in this delayed-treatment paradigm. These results suggest that the main beneficial effects of leptin after stroke are associated with its early neuroprotective role rather than with its proneurogenic or proangiogenic effects.

Multimodal reperfusion therapy for large hemispheric infarcts in octogenarians: is good outcome a realistic goal?

BACKGROUND AND PURPOSE: MMRT may be beneficial in a subset of patients with large hemispheric stroke who cannot be treated with systemic thrombolysis. Because most previous studies only included relatively young patients, the outcome of very old patients given MMRT remains unknown. MATERIALS AND METHODS: Consecutive patients with large hemispheric stroke treated with MMRT and admitted to intensive care were included. We compared neurologic and functional outcomes between patients younger and older than 80 years. RESULTS: We included 14 patients older than 80 years and compared them with 66 patients who were younger than 80. Cerebrovascular risk factor profile, admission NIHSS scores, stroke etiology and pathogenesis, and procedure-related variables did not differ between the groups except for a higher prevalence of smoking in younger patients. Excellent target vessel recanalization (Thrombolysis in Myocardial Infarction score of 3) and good outcome at 90 days (modified Rankin Score ≤ 2) were more common in younger patients (45% versus 14%, P = .047, and 41% versus 0%, P = .008, respectively). In contrast, mortality rates were higher in octogenarians (43% versus 17%, respectively). CONCLUSIONS: In this study, very old patients had higher chances of mortality and a very low probability of achieving functional independence even after MMRT. Further prospective studies are needed to examine the futility of MMRT in the very old.

Rehabilitation outcomes of stroke patients treated with multi-modal endovascular reperfusion therapy.

AIM: The aim of this study was to investigate the influence of multi-modal endovascular reperfusion therapy (MMRT) on functional outcomes following rehabilitation. METHODS: Data from 14 MMRT-treated patients were analyzed and compared to MMRT-ineligible, age and stroke severity-matched patients treated at the same Neurological and Rehabilitation departments. Neurological evaluation was assessed with the NIH stroke scale (NIHSS). Activity of daily living was measured using the FIMTM instrument. Functional outcome was measured using the modified Rankin scale (mRS). RESULTS: The baseline characteristics of both groups were similar. NIHSS scores were lower in the MMRT group and they had slightly better functional and rehabilitation scores on admission to rehabilitation. At the end of rehabilitation, more MMRT-treated patients reached functional independence (mRS≤2; 50% vs. 7% respectively P=0.03). FIM scores were also higher in the MMRT group (mean score 93.3 vs. 87.7, respectively) but the difference did not reach significance. The delta in FIM and NIHSS scores obtained during rehabilitation did not significantly differ between the groups. MMRT remained a significant modifier of good outcome after regression analysis (OR 21.5 95% CI 1.1-410). CONCLUSION: MMRT-treated patients have better chances of attaining independence after rehabilitation therapy. However, the additional improvements gained while in active rehabilitation were independent of reperfusion status.

Subacute treatment with vascular endothelial growth factor after traumatic brain injury increases angiogenesis and gliogenesis.

Vascular endothelial growth factor (VEGF) is neuroprotective and induces neurogenesis and angiogenesis when given early after traumatic brain injury (TBI). However, the effects of VEGF administration in the subacute phase after TBI remain unknown. Mice were subjected to TBI and treated with vehicle or VEGF beginning 7 days later for an additional 7 days. The animals were injected with BrdU to label proliferating cells and examined with a motor-sensory scale at pre-determined time points. Mice were killed 90 days post injury and immunohistochemistry was used to study cell fates. Our results demonstrate that lesion volumes did not differ between the groups confirming the lack of neuroprotective effects in this paradigm. VEGF treatment led to significant increments in cell proliferation (1.9 fold increase vs. vehicle, P<0.0001) and angiogenesis in the lesioned cortex (1.7 fold increase vs. vehicle, P=0.0001) but most of the proliferating cells differentiated into glia and no mature newly-generated neurons were detected. In conclusion, VEGF induces gliogenesis and angiogenesis when given 7 days post TBI. However, treated mice had only insignificant motor improvements in this paradigm, suggesting that the bulk of the beneficial effects observed when VEGF is given early after TBI results from the neuroprotective effects.

THR-18, a 18-mer peptide derived from PAI-1, is neuroprotective and improves thrombolysis by tPA in rat stroke models.

OBJECTIVE: The thrombolytic treatment of stroke is limited by a narrow therapeutic time window and is associated with significant adverse side effects. To improve this situation, the modulation of tissue-type plasminogen activator (tPA) activity by a synthetic plasminogen activator inhibitor-1-derived 18-mer peptide (THR-18) was examined in two models of stroke in rats. METHODS: In the first model (thromboembolic), stroke was induced by intra-carotid injection of micro-clots to rats, and tPA (6 mg/kg) was intravenously infused for 30 minutes with or without THR-18 (1 mg/kg) at 4 hours post-induction. In the second model [transient middle cerebral artery occlusion (tMCAO)], stroke was induced for 2 hours by a transient mechanical occlusion. tPA and/or THR-18 (0.02, 0.1, and 1 mg/kg) were intravenously infused for 60 minutes at the time of reperfusion. RESULTS: In the thromboembolic model, cerebral blood flow, measured before and up to 5.5 hours post-induction, revealed that tPA administration caused reperfusion of flow at 30 minutes post-infusion. Later on, an additional increase in reperfusion was seen in the tPA+THR-18 group, and not with tPA alone. In both models, the frequency of intracranial hemorrhage in the tPA-treated group was found to be significantly higher than the control, and this tPA effect was attenuated by THR-18. In the thromboembolic study, infarct size and brain edema were similar in the control and tPA-treated rats. However, the combination of tPA and THR-18 caused a statistically significant reduction in both parameters (infarct size 17.8 versus 25.0%, brain edema 5 versus 8%, tPA+THR-18 versus control, respectively). In the tMCAO mechanical model, infarct size and brain edema were both increased by tPA treatment as compared to the control group, and this increase was markedly diminished by THR-18 co-administration. Neurobehavioral assessment of the tMCAO animals performed at 72 hours post-stroke induction revealed significant improvements (P<0.05-0.01) in neuroscores in all groups of animals treated with peptide-tPA, as compared to the tPA monotherapy group. A significant (P<0.05) improvement in the neurological outcome was also seen in the THR-18 monoterapy group, as compared to the control animals, thus demonstrating a clear neuroprotective effect by the peptide on its own. DISCUSSION: The results support the use of THR-18 together with tPA in the thrombolytic therapy of stroke, in order to achieve better patency, less tPA-induced damage, and possibly a widening of tPA therapeutic time window.

Leptin induces neuroprotection neurogenesis and angiogenesis after stroke.

Leptin is a potent AMP kinase (AMPK) inhibitor that is central to cell survival. Hence, we explored the effects of leptin on neurogenesis and angiogenesis after stroke. Neural stem cells (NSC) were grown as neurospheres in culture and treated with vehicle or leptin and neurosphere size and terminal differentiation were then determined. We then explored the effects of leptin on endogenous repair mechanisms in vivo. Sabra mice underwent photothrombotic stroke, were given vehicle or leptin and newborn cells were labeled with Bromo-deoxy-Uridine. Functional outcome was studied with the neurological severity score for 90 days post stroke and the brains were then evaluated with immunohistochemistry. In a subset of animals the brains were also evaluated for changes in the expression of leptin receptor and AMPK. In vitro, leptin led to a 2-fold increase in neurosphere size but did not change the differentiation of newborn cells. Following stroke, exogenous leptin led to a 4-fold increase in the number of NSC in the cortex abutting the lesion. There was a 1.5-fold increase in the number of newborn neurons and glia in leptin treated animals. Leptin also significantly increased the number of blood vessels in the peri-lesioned cortex. Leptin treated mice had increased expression of leptin receptor and increased phosphorylated AMPK concentration. Animals treated with leptin also had significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations. This may explain at least in part the better functional outcome observed in leptin treated animals after stroke.

The function of the adrenocortical axis in permanent middle cerebral artery occlusion: effect of glucocorticoids on the neurological outcome.

We characterized the effect of acute ischemic stroke on the activation of the hypothalamic-pituitary-adrenal (HPA) axis and evaluated the role of glucocorticoids (GC) in the clinical outcome following ischemic stroke. Male spontaneous hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and developed a cortical infarct. At 4h post-PMCAO or sham operation, serum levels of ACTH and corticosterone (CS) were elevated 5 and 4 fold respectively as compared to controls and then returned to basal levels at 24h post surgery. In these experimental groups we found also a significant depletion of median eminence (ME)-CRH(41). In adrenalectomized (Adx) rats that underwent PMCAO the degree of motor disability and infarct volume was similar to that of intact rats. Administration of dexamethasone (Dex) to Adx-PMCAO rats significantly improved the motor disability and decreased the infarct volume. However, in sham-Adx with PMCAO, Dex had no effect on these two parameters. In rats with PMCAO or sham-PMCAO, brain production of PGE(2) was significantly increased. This effect was further enhanced in Adx-PMCAO rats and significantly inhibited by Dex. In conclusion, activation of the HPA axis following PMCAO is due to stress induced by surgery. This activation is mediated by hypothalamic CRH(41). Absence of endogenous GC or administration of Dex in naïve rats does not alter motor and pathological parameters in the acute stage following PMCAO. In contrast, administration of Dex significantly improved the outcome following cerebral ischemia in Adx rats which may be due to increased glucocorticoid receptors. Brain production of PGE(2) does not play an important role in the pathophysiology of the acute phase of cerebral ischemia.