Characterisation of Endothelin-1-Induced Intrastriatal Lesions Within the Juvenile and Adult Rat Brain Using MRI and 31P MRS

Abstract

Improved non-invasive magnetic resonance (MR) characterisation of in vivo models of focal ischaemic insults such as transient ischaemic attack (TIA) and perinatal arterial ischaemic stroke (AIS) may assist diagnosis, outcome prediction and treatment design. The classic middle cerebral artery occlusion (MCAO) model of ischaemic stroke is well documented in MR studies but generates extensive and complex lesions involving an acute inflammatory response and de-occlusion that immediately restores circulation. By contrast, intrastriatal microinjection of the potent vasoconstrictor, endothelin-1 (ET-1), induces a focal, reversible and low-flow ischaemia in the absence of a typical inflammatory response, which gradually restores blood flow over several hours and may be more relevant to TIA and AIS pathology. This study presents the first comprehensive longitudinal MR characterisation of the real-time anatomical [T1-weighted (T1-w)/T2-weighted (T2-w)], pathophysiological [apparent diffusion coefficient (ADC), cerebral blood volume, gadolinium contrast imaging of blood-brain barrier (BBB) integrity] and metabolic [phosphorus magnetic resonance spectroscopy (31P MRS)] evolution of a purely ischaemic ET-1-induced lesion within the juvenile and adult rat brain. ET-1-induced cytotoxic oedema was visualised on T2-w magnetic resonance imaging (MRI), inconsistent with the conventional notion that it cannot be detected using anatomical MRI. There was no immunohistochemical evidence of an acute inflammatory response or loss of BBB integrity, thus excluding a vasogenic oedema contribution to the pathology. Maximal T2-w intensity correlated with the lowest ADC value in both age groups, re-emphasising the purely ischaemic nature of the lesion and the absence of vasogenic oedema. Furthermore, extensive acute T1-w hypointensity was observed in the presence of cytotoxic oedema-induced T2-w changes, whereas other authors have shown that increased T1 values following MCAO reflect vasogenic oedema. Intriguingly, the lesion border exhibited hyperintensity on T2-w and ADC MRI at later time points, and the former may be a consequence of phagocytosis-induced fatty droplet deposition by macrophages detected immunohistochemically. In spite of a chronically reduced ADC, typically associated with ischaemia-induced energy failure, a 31P MRS-detectable reduction in the phosphocreatine (PCr) to gamma adenosine triphosphate (γATP) ratio was not observed at any time point in either age group, suggesting dissociation of tissue water diffusion and metabolic changes within the ET-1-induced lesion.