Studies of experimental brain trauma and ischemia : effects of Epo

Författare: Jonas Blixt; Karolinska Institutet; Karolinska Institutet; []

Nyckelord: ;

Sammanfattning: Traumatic brain injury has attained a lot of scientific and clinical focus during a considerable amount of time but is still as of today regarded a highly lethal condition with a high degree of morbidity amongst the surviving. The complexity of the pathophysiological processes that start immediately after the primary injury are challenging – disruption of the blood-brain barrier (BBB), imbalance in metabolic supply and demand, neuroinflammation and formation of brain edema are some of the components in a plethora of existing processes. The overall aim of this thesis was to characterize pathophysiological processes in brain injury (TBI and ischemia) and investigate effects of erythropoietin (EPO) on these processes, with focus on brain edema, blood-brain barrier, and astrocyte function. In an animal model of TBI we found that the resulting brain edema was caused by an early BBB disruption associated with a decrease in anchoring tight junction proteins as well as a cytotoxic edema and a decreased expression of the water channel aquaporin 4 (AQP4). The BBB disruption lasted for at least 4 days while levels of AQP4 was restored between day 1 and 4. We suggest that the vasogenic component of the edema, partly due to disruption of tight junctions in the BBB, likely is of importance in the early phase, and that the observed decrease in AQP4 expression may inhibit the later resolution of the edema. When analyzing the effect of EPO, we found that post-traumatic administration of daily doses of EPO preserved both structural and functional properties of the BBB by preventing loss of the tight junction component ZO-1, resulting in reduced IgG permeability and possibly water as well. Further, EPO treatment following TBI inhibited the decrease of AQP and cytotoxic brain edema. Most of these functions are related to astrocytes. We further explored effects of erythropoietin on astrocyte function and metabolism in an cell model of ischemia. We found that EPO had positive effects on astrocyte glutamate uptake and metabolism (lactate extrusion and NADH production) and that these effects, at least partly, were mediated by preservation of Na,K-ATPase activity, and function of the Na+/H+ exchanger. EPO may by these mechanisms protect against cytotoxicity and excitotoxicity and contribute to neuroprotection. Taken together our findings, by use of several techniques in cellular and animal-models, indicate that treatment with EPO decrease brain edema, restores BBB function, and have positive effects on glutamate clearance and metabolic functions in astrocytes. These effects are most likely mediated by EPOs anti-inflammatory, glycolysis stimulating, and mitochondria stabilizing functions, and can thereby have a potential neuroprotective role in TBI with secondary ischemic injury, and probably as well in primary brain ischemia. Taken together, as an extremely complex and highly vulnerable organ the brain will keep challenging scientists. We believe that these studies, including aspects regarding both TBI and ischemia, contributes to new insights regarding EPO or EPO-derivates potential beneficial effects in brain injury mechanisms.

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