Recent advances in stroke rehabilitation 2006.
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Humans↗
Biomedical subjects
Rajiv Ratan
Publications and source records attributed to Rajiv Ratan.
Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model.
Dimethyl sulfoxide (DMSO) has a variety of biological actions that suggest efficacy as a neuroprotectant. We (1) tested the neuroprotective potential of DMSO at different time windows on infarct size using 2,3,5-triphenyltetrazolium staining and (2) investigated the effects of DMSO on ischemia evolution using quantitative diffusion and perfusion imaging in a permanent middle cerebral artery occlusion (MCAO) model in rats. In experiment 1, DMSO treatment (1.5 g/kg intravenously over 3 h) reduced infarct volume 24 h after MCAO by 65% (P<0.00001) when initiated 20 h before MCAO, by 44% (P=0.0006) when initiated 1 h after MCAO, and by 17% (P=0.11) when started 2 h after MCAO. Significant infarct reduction was also observed after a 3-day survival in animals treated 1 h after MCAO (P=0.005). In experiment 2, treatment was initiated 1 h after MCAO and maps for cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were acquired before treatment and then every 30 mins up to 4 h. Cerebral blood flow characteristics and CBF-derived lesion volumes did not differ between treated and untreated animals, whereas the ADC-derived lesion volume essentially stopped progressing during DMSO treatment, resulting in a persistent diffusion/perfusion mismatch. This effect was mainly observed in the cortex. Our data suggest that DMSO represents an interesting candidate for acute stroke treatment.
Animals↗
Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.
Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.
Animals↗
New perspectives on developing acute stroke therapy.
The development of additional acute stroke therapies to complement and supplement intravenous recombinant tissue-type plasminogen activator within the first 3 hours after stroke onset remains an important and pressing need. Much has been learned about the presumed target of acute stroke therapy, the ischemic penumbra, and clinically available imaging modalities such as magnetic resonance imaging and computed tomography hold great promise for at least partially identifying this region of potentially salvageable ischemic tissue. Understanding the biology of ischemia-related cell injury has also evolved rapidly. New treatment approaches to improve outcome after focal brain ischemia will likely be derived by looking at naturally occurring adaptive mechanisms such as those related to ischemic preconditioning and hibernation. Many clinical trials previously performed with a variety of neuroprotective and thrombolytic drugs provide many lessons that will help to guide future acute stroke therapy trials and enhance the likelihood of success in future trials. Combining knowledge from these three areas provides optimism that additional acute stroke therapies can be developed to maximize beneficial functional outcome in the greatest proportion of acute stroke patients possible.
Acute Disease↗