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REAL-TIME MRI OF MESENCHYMAL STEM CELL DISTRIBUTION IN RAT BRAIN AFTER INTRA-ARTERIAL AND INTRAVENOUS TRANSPLANTATION IN EXPERIMENTAL STROKE
Background and Aims
Transplantation of mesenchymal stem cells (MSC) is a promising approach for ischemic stroke treatment. The investigation of cell fate after transplantation could be one of the key factors on the way to understand the mechanisms of therapeutic effects of transplanted cells. The aim of this work was to study precise distribution of MSC in ischemic rat brain starting from the first pass through cerebral vascularity after intra-arterial (IA) and intravenous (IV) administration using real-time MRI.
Human placenta MSC were transplanted IA (5x105cells,n=25) or IV (2x106cells,n=25) into male Wistar rats 24h after 90min MCAO. Administration of SPIO labeled cells were performed inside 7Т-MRI scanner, T2*WI with 1min resolution for IA and SWI with 7min resolution for IV administration were performed. MRI data was confirmed by histology.
After IA administration within first 5min MSC were detected in the periphery of the infarct core and brain stem, 15min later in the infarct core and contralateral hemisphere, after 30min the number of cells in all described regions reached their maximum. MSC were localized inside cerebral vessels in close contact with their walls. In case of IV administration MSC were visualized in both hemispheres only 15min after injection. MSC could no longer be detected in the brain 72h after IA and 24h after IV infusion.
The obtained data on MSC distribution and homing confirms the paracrine mechanism of action of transplanted cells after stroke. This work was financially supported by the grant of the Ministry of Science and Higher Education of Russian Federation №075-15-2020-792 (Unique identifier RF----190220X0031).
FLUOXETINE-INDUCED 5-HT AXONAL PLASTICITY IN BEHAVIOURAL RECOVERY FOLLOWING UNILATERAL PREFRONTAL CORTICAL ISCHEMIA
Background and Aims
Research using brain injury models indicates 5-HT axons can regrow and release 5-HT associated with behavioural recovery, after several months. However, the impact of selective serotonin transporter (SERT) inhibitor (SSRI) treatment on 5-HT axonal regeneration has not been tested. Fluoxetine increases synaptic serotonin (5-HT) levels to improve depressive/anxiety symptoms in stroke survivors. We hypothesized that chronic fluoxetine induces a novel 5-HT innervation in mPFC-limbic regions to recover from post-stroke depression (PSD).
We have reported a mouse model of PSD with no sensorimotor impairments using infusion of endothelin-1 to induce ischemia in the left medial-prefrontal cortex (LmPFC). The PSD mice were tested for depression and anxiety behaviour (1->6 wks post-stroke). Then they were perfused and fixed and brain sections stained for SERT, synaptophysin- gephyrin (inhibitory sites) and -PSD95 to label 5-HT processes and release sites, inhibitory and excitatory synapses. Confocal microscopic images were reconstructed to quantify the volume of SERT+ processes, the density of varicosities and the 5-HT synaptic contacts.
Chronic FLX mediated a full behavioral recovery in the PSD model. After 1-week post-stroke, 5-HT innervation was greatly reduced at the stroke site and the left basolateral amygdala (BLA). At 6 wks post-stroke 5-HT projections, varicosities and 5-HT terminals at excitatory or inhibitory synaptic sites remained reduced. However, fluoxetine induced a complete recovery in the 5-HT circuitry, including in ipsilesional LmPFC and BLA, particularly in contracts with inhibitory (gephyrin-positive) sites.
These findings highlight a novel role for SSRI-induced neuroplasticity of 5-HT projections in behavioral recovery in a model of PSD.
SAFINAMIDE AMELIORATES CEREBRAL ISCHEMIA-REPERFUSION INJURY IN RATS BY ATTENUATING OXIDATIVE STRESS, INFLAMMATION AND APOPTOSIS
Background and Aims
With spectacular failure in searching an adjunctive neuroprotective agent for ischemic stroke, exploring and repurposing an already approved drug has become a lower risk alternative. Safinamide, a recently approved drug for Parkinson’s disease, has shown neuroprotective effects in various diseases. The present study investigated the effect of safinamide in experimental model of ischemic stroke in rats.
Middle cerebral artery occlusion (MCAo) was performed in Sprague Dawley rats. Dose-selection (20, 40 and 80 mg/kg), therapeutic-time-window (ischemia/reperfusion I/R, post-reperfusion 0h/2h and post-reperfusion 2h/4h) and sub-acute (3-days) studies were performed. Effective dose and time-point were selected based on neurobehavioral parameters and infarct size reduction assessed 24h post-reperfusion. Study was extended for 72h. Effects on neurobehavioral parameters and infarct size reduction (MRI) were assessed. To explore the basis of neuroprotection, oxidative stress (MDA, GSH, SOD, NOX-2), inflammatory cytokines (TNF-α, IL-1β, IL-10) and apoptosis (Bax, Bcl-2, cleaved-caspase-3 expression and TUNEL staining) were studied.
Safinamide (80 mg/kg) given post-ischemia and -reperfusion (Saf I/R) and post-reperfusion (Saf 0h/2h) showed significant reduction in infarct size and improvement in neurobehavioral parameters. Safinamide (80 mg/kg) was administered post-reperfusion for 3-days. Significant improvement in motor-coordination and infarct size reduction (TTC staining and MRI) was observed. Additionally, safinamide treatment significantly improved altered redox homeostasis and inflammatory cytokine levels. The deranged expression of apoptotic markers and increased TUNEL positive cells in cortex after MCAo were significantly normalized with safinamide treatment.
The results demonstrated neuroprotective potential of safinamide in cerebral I/R injury and can be considered for repurposing in ischemic stroke.