MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

Abstract

Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes' occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies.

Chronic stress exposure following photothrombotic stroke is associated with increased levels of Amyloid beta accumulation and altered oligomerisation at sites of thalamic secondary neurodegeneration in mice

“…In experimental stroke models, SND occurs without exception. [12][13][14][15][16][17] The most dominant histological features of SND is neuronal loss concomitant with intense microglial activation. 12 We recently identified, using a preclinical model, that stress could exacerbate the extent of neuronal loss occurring at sites of SND.…”

Neuroprotective Effects of Salidroside on Cerebral Ischemia/Reperfusion-Induced Behavioral Impairment Involves the Dopaminergic System

“…Indeed, our data showed a similar observation: salidroside treatment prevented dopaminergic neurons loss as displayed by the preservation of TH-positive cells in the rat SNpc. Ischemic injury to the SN, a central output nucleus of the basal ganglia, may lead to neurobehavioral impairment (Prinz et al, 2015;Zhang et al, 2015). Therefore, the neuroprotective effect of salidroside in the SNpc against ischemic impairment may constitute the foundation for the elevation of behavioral function.…”

Inhibition of Cathepsins B Induces Neuroprotection Against Secondary Degeneration in Ipsilateral Substantia Nigra After Focal Cortical Infarction in Adult Male Rats

“…During the process of sudden cortical cerebral blood supply disturbance, secondary degeneration may occur at distant sites separate from the dominant vessels. It has been documented that secondary degeneration in the ipsilateral SNr after focal cortical stroke, in rodents, nonhuman primates, and humans ( Ohe et al, 2013 ; Rodriguez-Grande et al, 2013 ; Chen et al, 2015 ; Prinz et al, 2015 ). In this study, we electrocoagulated the MCA distal to striate branch, similar to what Xing et al (2012) did in rodent model.…”

“…SN is another brain structure located in the midbrain that is usually vulnerable to secondary degeneration after middle cerebral artery occlusion (MCAO) in animal experiments. Owing to its delayed occurrence, secondary damage can be a promising target for new neuroprotective strategies beyond the narrow time window for acute stroke therapy ( Prinz et al, 2015 ). Thus, this may be of significant clinical value.…”