Gene Expression Changes and Brain Plasticity after Experimental Stroke

Sammanfattning: Stroke is the most common life-threatening neurological disease and ranks as the third leading cause of death in major industrialized countries. It is also the leading cause of serious long-term disability and about sixty percent of survivors have disabilities in their extremities. Recovery of certain neurological functions occurs over time, which has been attributed to endogenous restorative processes in areas adjacent and remote from the infarct area. The area adjacent to infarct, the peri-infarct area, shows activation of processes pertinent for recovery such as enhanced cellular excitability and axonal sprouting. The major objective of this thesis has been to unravel some aspects of functional recovery following stroke. In Paper I, we undertook a comprehensive investigation of gene expression changes in the peri-infarct area during the first 24 h after insult using large-scale array technology. Several genes associated with tissue regeneration and recovery, were activated early after the ischemic insult. In particular, we identified genes related to lipid transport and myelin formation as well as genes involved in synaptic plasticity. This suggests that parallel to cell death signaling and ensuing cell death in severely injured areas, repair processes are induced in the adjacent surviving areas. In Paper II and II, we characterized expression of transcriptional regulators/effectors most likely implicated in adaptation/stress response of the peri-infarct area. The second part of the thesis focused on the long-term recovery period (0-30 days) following stroke. In Paper IV, we investigated the role of Apolipoprotein D, a transport protein known to be important for lipid trafficking. ApoD accumulated along the rim of the infarct during the first week of recovery and was localized to oligodendrocytes. We believe that this expression is associated with regeneration of the peri-infarct area and ApoD may function as a lipid carrier providing myelinating oligodendrocytes with cholesterol for axonal regeneration. Further, housing animals in an enriched setting during the post-ischemic period elicited increased levels of ApoD and this was associated with an improved functional recovery. In Paper V, we showed that administration of a receptor ligand, initiated two days following insult, enhanced functional recovery. The mechanisms of this recovery enhancing effects were attributed to stimulation of axonal outgrowth and possibly regulation of lipid transport in the peri-infarct area. The last two studies reveal novel aspects of recovery by emphasizing the importance of lipid trafficking for formation of new connections of the brain. Overall, this thesis shows that the injured brain activates repair processes early after an ischemic insult and that these events can be stimulated by either pharmacology and/or enriched environment. Delaying commencement of pharmacological treatment for days after injury still results in an improvement in functional outcome. This finding together with other reports strongly argue that the therapeutic time window after stroke is much more extensive than previously believed. Eligible future stroke therapies must consider beyond the acute phase of cell death and focus on enhancement of post-injury plasticity.