Combined enriched environment÷atipamezole treatment transiently improves sensory functions in stroke rats independent from neurogenesis and angiogenesis.

Functional recovery after cerebral ischemia may be enhanced by activation of the noradrenergic system and by environmental enrichment. The underlying mechanisms have remained elusive, but endogenous neurogenesis and perilesional angiogenesis have been speculated to contribute to the behavioral improvement. To address this question, neurogenesis in the subventricular zone (SVZ) and perilesional angiogenesis (RECA-1) were correlated with behavioral performance in forty Wistar rats subjected to transient middle cerebral artery occlusion (MCAO) or sham-operation. Atipamezole, an α2-adrenoreceptor antagonist (1 mg÷kg, i.p.), was administered for 10 days together with housing of rats in an enriched environment. MCAO rats and sham-operated rats housed in single non-enriched cages were used as controls. Histological analysis after 28-day behavioral follow-up showed a massive increase in doublecortin (DCX)-positive cells in the SVZ both in MCAO rats housed in single cages and in the enriched environment together with atipamezole treatment whereas perilesional RECA-1 staining for new blood vessels was not altered. Time to the first contact and time to remove sticky stimuli from the forelimbs indicated improved sensory processing, which disappeared after cessation of atipamezole administration. Skilled forelimb use as measured by performance in Montoya's staircase test was not affected by the treatment. There were no correlations between behavioral measures and histology. Thus, sensory facilitation or reversal of hypometabolism by the combined therapy may be the mechanism accounting for the improved behavior after stroke independent from neurogenesis and angiogenesis.

Human bone marrow mesenchymal stem/stromal cells produce efficient localization in the brain and enhanced angiogenesis after intra-arterial delivery in rats with cerebral ischemia, but this is not translated to behavioral recovery.

Intravascular cell therapy is a promising approach for the treatment of stroke. However, high accumulation of cells to lungs and other filtering organs is a major concern after intravenous (i.v.) cell transplantation. This can be circumvented by intra-arterial (i.a.) cell infusion, which improves homing of cells to the injured brain. We studied the effect of i.a. delivery of human bone marrow-derived mesenchymal cells (BMMSCs) on behavioral and histological outcome in rats after middle cerebral artery occlusion (MCAO). Sixty male Wistar rats were subjected to transient MCAO (60 min) or sham-operation. BMMSCs (1×10(6)) were infused into the external carotid artery on postoperative day 2 or 7. Histology performed after a 42-day follow-up did not detect any human cells (MAB1281) in the ischemic brain. Endothelial cell staining with RECA-1 revealed a significant increase in the number of blood vessels in the perilesional cortex in MCAO rats treated with cells on postoperative day 7. Behavioral recovery as assessed in three tests, sticky label, cylinder and Montoya's staircase, was not improved by human BMMSCs during the follow-up. In conclusion, human BMMSCs did not improve functional recovery in MCAO rats despite effective initial homing to the ischemic hemisphere and enhanced angiogenesis, when strict behavioral tests not affected by repeated testing and compensation were utilized.

Non-selective calcium channel blocker bepridil decreases secondary pathology in mice after photothrombotic cortical lesion.

Experimental studies have identified a complex link between neurodegeneration, ß-amyloid (Aß) and calcium homeostasis. Here we asked whether early phase ß-amyloid pathology in transgenic hAPPSL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPPSL (n = 33) and non-transgenic (n = 30) male mice (4-5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Aß and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Aß and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P<0.05) and ischemia-induced rodent Aß accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P<0.01). Bepridil decreased calcium load in the thalamus (P<0.01). The present data suggest less pronounced primary and secondary pathology in hAPPSL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia.

Gait impairment in a rat model of focal cerebral ischemia.

The availability of proper tests for gait evaluation following cerebral ischemia in rats has been limited. The automated, quantitative CatWalk system, which was initially designed to measure gait in models of spinal cord injury, neuropathic pain, and peripheral nerve injury, is said to be a useful tool for the study of motor impairment in stroke animals. Here we report our experiences of using CatWalk XT with rats subjected to transient middle cerebral artery occlusion (MCAO), during their six-week followup. Large corticostriatal infarct was confirmed by MRI in all MCAO rats, which was associated with severe sensorimotor impairment. In contrast, the gait impairment was at most mild, which is consistent with seemingly normal locomotion of MCAO rats. Many of the gait parameters were affected by body weight, walking speed, and motivation despite the use of a goal box. In addition, MCAO rats showed bilateral compensation, which was developed to stabilize proper locomotion. All of these interferences may confound the data interpretation. Taken together, the translational applicability of CatWalk XT in evaluating motor impairment and treatment efficacy remains to be limited at least in rats with severe corticostriatal infarct and loss of body weight.