Abstract
The increased risk and prevalence of lacunar stroke and Parkinson's disease (PD) makes the search for better experimental models an important requirement for translational research. In this study we assess ischemic damage of the nigrostriatal pathway in a model of lacunar stroke evoked by damaging the perforating arteries in the territory of the substantia nigra (SN) of the rat after stereotaxic administration of endothelin-1 (ET-1), a potent vasoconstrictor peptide. We hypothesized that transplantation of neural stem cells (NSCs) with the capacity of differentiating into diverse cell types such as neurons and glia, but with limited proliferation potential, would constitute an alternative and/or adjuvant therapy for lacunar stroke. These cells showed neuritogenic activity in vitro and a high potential for neural differentiation. Light and electron microscopy immunocytochemistry was used to characterize GFP-positive neurons derived from the transplants. 48 h after ET-1 injection, we characterized an area of selective degeneration of dopaminergic neurons within the nigrostriatal pathway characterized with tissue necrosis and glial scar formation, with subsequent behavioral signs of Parkinsonism. Light microscopy showed that grafted cells within the striatal infarction zone differentiated with a high yield into mature glial cells (GFAP-positive) and neuron types present in the normal striatum. Electron microscopy revealed that NSCs-derived neurons integrated into the host circuitry establishing synaptic contacts, mostly of the asymmetric type. Astrocytes were closely associated with normal small-sized blood vessels in the area of infarct, suggesting a possible role in the regulation of the blood brain barrier and angiogenesis. Our results encourage the use of NSCs as a cell-replacement therapy for the treatment of human vascular Parkinsonism.
Highlights
Stroke is the second most common cause of death and major cause of disability worldwide, and most therapies have focused on early neuroprotection as a treatment strategy (Sahota and Savitz, 2011)
In general a better efficacy of cell transplantion was obtained by using neural-differentiated cells generated from immature neural stem cells (NSCs), which were allowed to differentiate for five days and which were collected by mild trypsinization
Adjacent regions to ischemic striatal areas, including the cerebral cortex, globus pallidus, and thalamus, lacked signs of vascular affectation (Figures 1A–E), suggesting that lacunar infarction was limited to the nigrostriatal pathway and cerebellum
Summary
Stroke is the second most common cause of death and major cause of disability worldwide, and most therapies have focused on early neuroprotection as a treatment strategy (Sahota and Savitz, 2011). Lacunar infarcts caused by occlusion of deep penetrating branches of major cerebral arteries are responsible for about 25% of all strokes (Sudlow and Warlow, 1997) and may cause idiopathic Parkinson’s disease (PD), in the elderly and as a consequence of drug abuse (Winslow et al, 2007). The increased risk and prevalence of lacunar stroke with PD (Becker et al, 2010) makes the search for experimental translational models necessary (Bailey et al, 2009; Martinez-Murillo et al, 2009). In this paper ischemic damage of the nigrostriatal path as a model of lacunar stroke was performed by affecting perforating arteries in the rat substantia nigra (SN) territory, following stereotaxic administration of the potent vasoconstrictor peptide endothelin-1 (ET-1) in the rat (Sharkey et al, 1993). Peptide ET-1 mediates a strong contractile effect on cerebral arteries, through the ETa subtype receptor which are mainly located on smooth muscle cells, whereas a vasodilatory response is mediated by ETb receptor activation
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