The CNS can exhibit features of inflammation in response to injury, infection or disease, whereby resident cells generate inflammatory mediators, including cytokines, prostaglandins, free radicals and complement, chemokines and adhesion molecules that recruit immune cells, and activate glia and microglia. Cerebral ischaemia triggers acute inflammation, which exacerbates primary brain damage. The regulation of inflammation after stroke is multifaceted and comprises vascular effects, distinct cellular responses, apoptosis and chemotaxis. There are many cell types that are affected including neurons, astrocytes, microglia and endothelial cells, all responding to the resultant neuroinflammation in different ways. Over the past 20 years, researchers examining brain tissue at various time intervals after stroke observed the presence of inflammatory cells, neutrophils and monocytes at the site of injury, as well as the activation of endogenous glia and microglia. This review examines the involvement of these cells in the progression of neural injury and proposes that the Toll-like receptors (TLRs) are likely to be an integral component in the communication between the CNS and the periphery. This receptor system is the archetypal pathogen sensing receptor system and its presence and signalling in the brain following neural injury suggests a more diverse role. We propose that the TLR system presents excellent pharmacological targets for the design of a new generation of therapeutic agents to modulate the inflammation that accompanies neural injury.

Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ-or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA À/À mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke-neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.

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Neuroinflammation is critical in the neural cell death seen in stroke. It has been shown that CNS and peripheral responses drive this neuroinflammatory response in the brain. The Toll-like receptors (TLRs) are important regulators of inflammation in response to both exogenous and endogenous stressors. Taking advantage of a downstream adapter molecule that controls the majority of TLR signalling, this study investigated the role of the TLR adaptor protein myeloid differentiation factor 88 (MyD88) in the control of CNS and peripheral inflammation. Reversible middle-cerebral artery occlusion was used as the model of stroke in vivo; in vitro primary cultured neurons and glia were subject to four hours of oxygen and glucose deprivation (OGD). Both in vitro and in vivo Myd88−/− animals or cells were compared with wild type (WT). We found that after stroke Myd88−/− animals have a larger infarct volume compared to WT animals. Interestingly, in vitro there was no difference between the survival of Myd88−/− and WT cells following OGD, suggesting that peripheral responses were influencing stroke outcome. We therefore generated bone marrow chimeras and found that Myd88−/− animals have a smaller stroke infarct than their radiation naive counterparts if their hematopoietic cells are WT. Furthermore, WT animals have a larger stroke than their radiation naive counterparts if the hematopoietic cells are Myd88−/−. We have demonstrated that MyD88-dependent signalling in the hematopoietic cell lineage reduces infarct size following stroke and that infiltrating cells to the site of neuroinflammation are neuroprotective following stroke.

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