Mesenchymal stem cells in the treatment of ischemic stroke

Over the past two decades, multiple preclinical studies have shown that transplantation of mesenchymal stem cells leads to a pronounced positive effect in animals with experimental stroke. Based on the promising results of preclinical studies, several clinical trials on the transplantation of mesenchymal stem cells to stroke patients have also been conducted. In this review, we present and analyze the results of completed clinical trials dedicated to the mesenchymal stem cells transplantation in patients with ischemic stroke. According to the obtained results, it can be concluded that transplantation of mesenchymal stem cells is safe and feasible from the economic and biomedical point of view. For the further implementa-tion of this promising approach into the clinical practice, randomized, placebo-controlled, multicenter clinical trials are needed with a large sample of patients and optimized cell transplantation protocols and patient inclusion criteria. In this review we also discuss possi-ble strategies to enhance the effectiveness of cell therapy with the use of mesenchymal stem cells

Combined Cell Therapy in the Treatment of Neurological Disorders

Cell therapy of neurological diseases is gaining momentum. Various types of stem/progenitor cells and their derivatives have shown positive therapeutic results in animal models of neurological disorders and in clinical trials. Each tested cell type proved to have its advantages and flaws and unique cellular and molecular mechanism of action, prompting the idea to test combined transplantation of two or more types of cells (combined cell therapy). This review summarizes the results of combined cell therapy of neurological pathologies reported up to this point. The number of papers describing experimental studies or clinical trials addressing this subject is still limited. However, its successful application to the treatment of neurological pathologies including stroke, spinal cord injury, neurodegenerative diseases, Duchenne muscular dystrophy, and retinal degeneration has been reported in both experimental and clinical studies. The advantages of combined cell therapy can be realized by simple summation of beneficial effects of different cells. Alternatively, one kind of cells can support the survival and functioning of the other by enhancing the formation of optimum environment or immunomodulation. No significant adverse events were reported. Combined cell therapy is a promising approach for the treatment of neurological disorders, but further research needs to be conducted

Long-term monitoring of chronic demyelination and remyelination in a rat ischemic stroke model using macromolecular proton fraction mapping

Remyelination is a key process enabling post-stroke brain tissue recovery and plasticity. This study aimed to explore the feasibility of demyelination and remyelination monitoring in experimental stroke from the acute to chronic stage using an emerging myelin imaging biomarker, macromolecular proton fraction (MPF). After stroke induction by transient middle cerebral artery occlusion, rats underwent repeated MRI examinations during 85 days after surgery with histological endpoints for the animal subgroups on the 7th, 21st, 56th, and 85th days. MPF maps revealed two sub-regions within the infarct characterized by distinct temporal profiles exhibiting either a persistent decrease by 30%–40% or a transient decrease followed by return to nearly normal values after one month of observation. Myelin histology confirmed that these sub-regions had nearly similar extent of demyelination in the sub-acute phase and then demonstrated either chronic demyelination or remyelination. The remyelination zones also exhibited active axonal regrowth, reconstitution of compact fiber bundles, and proliferation of neuronal and oligodendroglial precursors. The demyelination zones showed more extensive astrogliosis from the 21st day endpoint. Both sub-regions had substantially depleted neuronal population over all endpoints. These results histologically validate MPF mapping as a novel approach for quantitative assessment of myelin damage and repair in ischemic stroke

The Impact of Cerebral Perfusion on Mesenchymal Stem Cells Distribution after Intra-Arterial Transplantation: A Quantitative MR Study

Intra-arterial (IA) mesenchymal stem cells (MSCs) transplantation providing targeted cell delivery to brain tissue is a promising approach to the treatment of neurological disorders, including stroke. Factors determining cell distribution after IA administration have not been fully elucidated. Their decoding may contribute to the improvement of a transplantation technique and facilitate translation of stroke cell therapy into clinical practice. The goal of this work was to quantitatively assess the impact of brain tissue perfusion on the distribution of IA transplanted MSCs in rat brains. We performed a selective MR-perfusion study with bolus IA injection of gadolinium-based contrast agent and subsequent IA transplantation of MSCs in intact rats and rats with experimental stroke and evaluated the correlation between different perfusion parameters and cell distribution estimated by susceptibility weighted imaging (SWI) immediately after cell transplantation. The obtained results revealed a certain correlation between the distribution of IA transplanted MSCs and brain perfusion in both intact rats and rats with experimental stroke with the coefficient of determination up to 30%. It can be concluded that the distribution of MSCs after IA injection can be partially predicted based on cerebral perfusion data, but other factors requiring further investigation also have a significant impact on the fate of transplanted cells

Dynamic MRI of the Mesenchymal Stem Cells Distribution during Intravenous Transplantation in a Rat Model of Ischemic Stroke

Systemic transplantation of mesenchymal stem cells (MSCs) is a promising approach for the treatment of ischemia-associated disorders, including stroke. However, exact mechanisms underlying its beneficial effects are still debated. In this respect, studies of the transplanted cells distribution and homing are indispensable. We proposed an MRI protocol which allowed us to estimate the dynamic distribution of single superparamagnetic iron oxide labeled MSCs in live ischemic rat brain during intravenous transplantation after the transient middle cerebral artery occlusion. Additionally, we evaluated therapeutic efficacy of cell therapy in this rat stroke model. According to the dynamic MRI data, limited numbers of MSCs accumulated diffusely in the brain vessels starting at the 7th minute from the onset of infusion, reached its maximum by 29 min, and gradually eliminated from cerebral circulation during 24 h. Despite low numbers of cells entering brain blood flow and their short-term engraftment, MSCs transplantation induced long lasting improvement of the neurological deficit, but without acceleration of the stroke volume reduction compared to the control animals during 14 post-transplantation days. Taken together, these findings indicate that MSCs convey their positive action by triggering certain paracrine mechanisms or cell–cell interactions or invoking direct long-lasting effects on brain vessels

The Effect of a New N-hetero Cycle Derivative on Behavior and Inflammation against the Background of Ischemic Stroke

Ischemic stroke triggers a whole cascade of pathological changes in the brain, one of which is postischemic inflammation. Since in such cases thrombolytic therapy is often not possible, methods that modulate inflammation and affect microglia become particularly interesting. We synthesized 3-(2-oxo-4-phenylpyrrolidin-1-yl)propane-1-sulfonate calcium(II) (Compound 4) and studied its anti-inflammatory activity in in vitro and in vivo models of inflammation and ischemia. Macrophage cell line RAW 264.7 was treated with lipopolysaccharides (LPS) and Compound 4 at various dosages to study the cytokine profile using real-time PCR and cytometric bead array (CBA). Stroke in rats was simulated by the middle cerebral artery occlusion method (MCAO). Several tests were performed to characterize the neurological deficit and locomotor activity of the rats, and afterwards, postmortem, the number of astrocytes was counted using immunohistochemistry. Compound 4 in in vitro tests dose-dependently reduced the expression of interleukin-1β (IL1β), and inducible nitric oxide synthase (iNOS) genes in cell culture and increased the concentration of cytokines: interleukin-2, 4, 6 (IL-2, IL-4, and IL-6). In vivo Compound 4 increased the orienting-exploratory behavior, and reduced neurological and motor deficit. The number of astrocytes that promote and support inflammation was lower in the group treated with Compound 4. The stroke volume measured by magnetic resonance imaging (MRI) showed no difference. We have shown that Compound 4 demonstrates anti-inflammatory activity by increasing the synthesis of anti-inflammatory and reducing pro-inflammatory cytokines, and positively affects the neurological deficit in rats. Thus, Compound 4 has a high therapeutic potential in the management of patients after a stroke and requires further study of its neuroprotective properties

A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions