12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi after Subarachnoid Hemorrhage in Mice.

Background and Purpose: Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus 12/15-LOX is an important target to prevent delayed cerebral ischemia. Methods: SAH was induced in C57BL/6 and 12/15-LOX-/- mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. Results: In SAH mice, 12/15-LOX was upregulated in brain vascular cells and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Conclusions: Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.

Dermatoglyphic correlates of hippocampus volume: Evaluation of aberrant neurodevelopmental markers in antipsychotic-naïve schizophrenia.

Schizophrenia is a disorder of aberrant neurodevelopment is marked by abnormalities in brain structure and dermatoglyphic traits. However, the link between these two (i.e. dermatoglyphic parameters and brain structure) which share ectodermal origin and common developmental window has not been explored extensively. The current study examined dermatoglyphic correlates of hippocampal volume in antipsychotic-naïve schizophrenia patients in comparison with matched healthy controls. Ridge counts and asymmetry measures for palmar inter-digital areas (a-b, b-c, c-d) were obtained using high resolution digital scans of palms from 89 schizophrenia patients [M:F=48:41] and 48 healthy controls [M:F=30:18]. Brain scans were obtained for subset of subjects including 26 antipsychotic-naïve patients [M:F=13:13] and 29 healthy controls [M:F=19:10] using 3 T-MRI. Hippocampal volume and palmar ridge counts were measured by blinded raters with good inter-rater reliability using valid methods. Directional asymmetry (DA) of b-c and bilateral hippocampal volume were significantly lower in patients than controls. Significant positive correlation was found between DA and ridge count of b-c with bilateral anterior hippocampal volume. Study demonstrates the utility of dermatoglyphic markers in identifying structural changes in the brain which may form the basis for neurodevelopmental pathogenesis in schizophrenia.

Clinical correlates of caudate volume in drug-naïve adult patients with obsessive-compulsive disorder.

The neurobiological basis of obsessive-compulsive disorder (OCD) has been theorized to reflect a dysfunction of cortico-striato-thalamo-cortical circuits, of which the caudate nucleus forms a critical component. However, structural imaging studies of the caudate in OCD are relatively scarce. To ascertain the clinical correlates of caudate volume in OCD, we report magnetic resonance imaging findings in a large sample of drug-naïve OCD patients in comparison with group-matched healthy controls. In this study, caudate volume was measured in coronal magnetic resonance brain images (high resolution 1-mm slice thickness) of 49 DSM-IV OCD patients and compared with that of 39 matched healthy controls. The caudate volume was measured separately for the head and body of the caudate. Analysis of covariance (ANCOVA) did not reveal significant differences in caudate volume between OCD patients and controls (whole group), with age, sex and intracranial volume as covariates. However, on examining the sexual dimorphism in the volume differences, male patients compared to male controls had significantly larger right caudate volume. The volume of the left caudate body showed a significant negative correlation with the total severity score on the Yale-Brown Obsessive-Compulsive Scale (YBOCS) on partial correlation analysis. Our study failed to show significant differences in caudate volumes between OCD patients and controls. However, it demonstrated a robust relationship between volume of the left caudate body and the severity of OCD. Additionally, there was a sexual dimorphism in caudate volume in OCD.