Non-invasive characterization of beta-amyloid(1-40) vasoactivity by functional magnetic resonance imaging in mice.

Neurovascular regulation, which is critical to the efficient functioning of the brain, is impaired in Alzheimer's disease and in transgenic mice overexpressing Abeta. Although senile plaques and neurofibrillary tangles represent neuropathological hallmarks of Alzheimer's disease, deposition of Abeta in cerebral blood vessels also likely plays a significant role in this debilitating and fatal disease. Further, soluble Abeta, which shows greater correlation with disease progression and severity than deposited plaques or tangles, displays strong vasoactive properties. The aim of this study was to develop a non-invasive model of cerebral vasoactivity that would ultimately be translatable to Alzheimer's disease as a marker for disease-modifying efficacy of novel small molecule and biologics drugs. Relative changes in cerebral blood volume following relevant doses of soluble Abeta(1-40) (0.01 or 0.1 mg/mouse), PBS, or the reverse peptide, Abeta(40-1) (0.01 or 0.1 mg/mouse), were monitored non-invasively by contrast-enhanced functional magnetic resonance imaging in anesthetized C57BL/6 mice. Experiments were performed on a 7T horizontal bore scanner using gradient echo echo-planar imaging. As expected, PBS and Abeta(40-1) did not induce any significant change in vascular response. In contrast, Abeta(1-40) significantly decreased CBV in a quantifiable, dose-related and region-specific manner. These data demonstrate for the first time the feasibility of characterizing pathogenic Abeta(1-40)-induced vascular dysfunction in vivo using a non-invasive approach. Further, this technique can be readily applied to preclinical screening in a longitudinal manner for novel drugs or antibodies targeting disease modification.

Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI.

BACKGROUND AND PURPOSE: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. EXPERIMENTAL APPROACH: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. KEY RESULTS: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. CONCLUSION AND IMPLICATIONS: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.