Beneficial effect of amyloid beta after controlled cortical impact.

BACKGROUND: Worse functional outcomes after controlled cortical impact (CCI) in Bace1(-/-) mice have previously been demonstrated. This study investigated whether reconstitution of amyloid-beta (Aß) after CCI in Bace1(-/-) animals would reverse the detrimental effect of Bace1 deletion. METHODS: Bace1(-/-) and wild type Bace1(+/+) (C57Bl/6) mice were subjected to CCI (n = 14-23/group) or sham injury (n = 6/group). After injury, mice underwent intracerebroventricular injections of Aß40 (n = 23 Bace1(-/-) and 17 Bace1(+/+) per group) or vehicle (n = 14 Bace1(-/-) and 22 Bace1(+/+) per group). Functional outcomes were assessed with wire grip (motor) and Morris water maze (spatial memory). Soluble Aß levels were assessed at 24 hours and 21 days after CCI. Lesion volume was assessed 21 days after injury. RESULTS: At 24 hours after injury, Aß-treated Bace1(-/-) mice had Aß40 levels similar to vehicle-treated Bace1(+/+) mice, but by 21 days after injury there were no differences between Aß-treated versus vehicle-treated Bace1(-/-) mice. Reconstitution with Aß40 improved motor but not spatial memory or histopathological outcome in injured Bace1(-/-) mice. In contrast, treatment with Aß40 worsened motor performance in Bace1(+/+) mice. CONCLUSIONS: The data suggest Aß40 may have some beneficial effects after CCI in young adult mice and that therapies targeting BACE should be approached cautiously.

Statin potentiates human platelet eNOS activity without enhancing eNOS mRNA and protein levels.

BACKGROUND/AIMS: Experimental studies suggest an enhanced endothelial and platelet nitric oxide (NO) generation after statin treatment, possibly due to increased endothelial NO synthase (eNOS) activity and protein levels. In parallel with experimental research, statins were shown to increase the forearm blood flow independently of serum cholesterol in humans. However, it was not possible to correlate blood flow changes with eNOS levels in these studies due to limitations in obtaining arterial samples. Hence, we investigated changes in eNOS activity, mRNA and protein levels after statin treatment in human platelets, which are readily accessible unlike arteries. METHODS: In vitro bleeding times were measured in 22 patients by stimulating platelets with collagen-epinephrine or collagen-ADP. To assess platelet eNOS activity, the bleeding times were also determined after incubating platelets with L-arginine. The measurements were repeated following 14 days of pravastatin (40 mg/day) treatment. Platelet-rich plasma was collected before and after statin treatment to evaluate eNOS mRNA (semiquantitative RT-PCR) and protein levels (Western blotting). RESULTS: The basal bleeding time was prolonged by 24 +/- 3% (mean +/- SE) when the samples were incubated with 500 microM of L-arginine. The NOS inhibitor L-N(5)-(I-iminoethyl)ornithine reversed this effect, suggesting that it was mediated by NO. After statin treatment, the NO-mediated prolongation of the bleeding time with 500 microM of L-arginine was significantly potentiated (to 44 +/- 10%). Despite enhanced eNOS activity, there was no significant change in platelet eNOS mRNA and protein levels after statin treatment. CONCLUSION: These data demonstrate that platelet eNOS activity is potentiated after statin treatment in humans in parallel with experimental studies.

fMRI of delayed albumin treatment during stroke recovery in rats: implication for fast neuronal habituation in recovering brains.

Accumulating experimental and clinical data suggest that albumin may be neuroprotective for stroke. Here, we use functional magnetic resonance imaging (fMRI) to evaluate the therapeutic efficacy of albumin and its effects on the recovery of stimuli-induced cerebral hemodynamics. For this purpose, fMRI activity in the ipsilesional somatosensory (SS) cortex was assessed using a well established rat model of transient 90 min focal ischemia and electrical forelimb stimulation. Rats were treated with either saline or albumin via intracerebroventricular injections at 12 h post-stroke onset. Despite this delayed treatment time, when compared to the saline-treated rats (n=7), there were significant enhancements of the fMRI activation in the albumin-treated rats (n=6) for both blood oxygenation level dependence (BOLD) and functional cerebral blood volume (fCBV) responses. Interestingly, the temporal characteristics of the ipsilesional SS BOLD responses in the albumin-treated rats appeared considerably altered compared to those of contralesional responses while such temporal alterations were not pronounced for the fCBV responses. These characteristic fMRI temporal profiles of the albumin-treated brains may be due to altered neuronal responses rather than altered integrity of neurovascular coupling, which implies an unusually fast habituation of neuronal responses in the lesional SS cortex. The correlation between various MRI-derived structural parameters and the fMRI response magnitude was also characteristic for albumin and control groups. Taken together, these data suggest that restoration of fMRI response magnitudes, temporal profiles, and correlations with structure may reveal the extent and specific traits of albumin treatment associated stroke recovery.