Module VII. Amyotrophic lateral

                              sclerosisStroke

Greg Albers & Midori Yenari

Neurology 205, Clinical Neuroscience, Fall Quarter, 2000-2001

This lecture will focus on the pathophysiological events which occur following a stroke, and potential therapeutic strategies which may reverse or attenuate injury. Strokes are caused by a disruption of blood flow to the brain. Most strokes are due to blockages of the cerebral vessel either by atherosclerotic disease or an embolus (most often a blood clot) which arises elsewhere (typically within the heart) and travels to the brain. A smaller percentage of stroke are caused by rupture of the blood vessels resulting in hemorrhage.
        Normal cerebral blood flow (CBF) is about 50 ml/100 g/ min. Thresholds of cerebral dysfunction occur with CBF reductions in the range of 16-20 ml/100 g/min (cerebral electrical silence). Ionic pump failure and loss of ion homeostasis begins with reductions to 10-12 ml/100 g/min, and cell death with CBF reductions less than 10 ml/ 100 g/min. These thresholds are also temporally dependent, that is, the longer blood flow is reduced, the more likely irreversible injury has taken place. Within brain regions affected by stroke, there is a region at the periphery of the infarct which is variably perfused depending on the collateral circulation. This may represent viable tissue if blood flow is quickly restored, or if the cells are "rescued" with a neuroprotective compound. This region is referred to as the ischemic penumbra, whereas regions which are irreversibly injured are called the ischemic core.
        Pathological processes which occur following stroke include accumulation of excitatory amino acids including glutamate which then activate their receptors leading to toxic increases in intracellular calcium and other ions. This increase in calcium leads to activation of various proteases ultimately leading to cell death. Mitochondria are also damaged following stroke, and lead to accumulation of free radicals, particularly when the occluded vessel is reopened. This leads to secondary injury where high levels of reactive oxygen species enter the brain tissue in an already energetically compromised system. Reactive oxygen species can lead to direct tissue damage, and can also damage mitochondria and initiate programmed cell death (apoptosis) under certain circumstances. The inflammatory response is also activated in the presence of necrotic tissue, as evidenced by activation of the brain's resident immune cell, the microglia. The peripheral inflammatory response also participates in ischemic damage where reperfusion can lead to tissue influx of leukocytes. Immune cells cause more damage by releasing toxic mediators such as free radicals, nitric oxide, glutamate, proteases and inflammatory cytokines. Knowledge of the various processes which occur during stroke has led to the development of various therapies directed at one or more of these pathways.
 

Papers for discussion by Benjamin Hoehn  and Geoffrey Meissner:

Davis, S. M., Lees, K. R., Albers, G. W., Diener, H. C., Markabi, S., Karlsson, G., and Norris, J. Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist. Stroke 31: 347-354, 2000.
Abstract: BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS: The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS: Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia

Perez-Pinzon, M. A., Maier, C. M., Yoon, E. J., Sun, G. H., Giffard, R. G., and Steinberg, G. K. Correlation of CGS 19755 neuroprotection against in vitro excitotoxicity and focal cerebral ischemia. J.Cereb.Blood Flow Metab 15: 865-876, 1995.
Abstract: The in vivo neuroprotective effect and brain levels of cis-4- phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from feta mice were injured by exposure to 500 microM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 micro M, and against OGD the ED50 was 15.2 microM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 microM and 5 microM, respectively, at 1 h, 6 microM and 5 microM at 2 h, and 13 microM and 7 microM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood- brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection