Sequential combined Treatment of Pifithrin-α and Posiphen Enhances Neurogenesis and Functional Recovery After Stroke

Abstract

Objective:Although cerebral ischemia can activate endogenous reparative processes, such as proliferation of endogenous neural stem cells (NSCs) in the subventricular zone (SVZ) and subgranular zone (SGZ), the majority of these new cells die shortly after injury and do not appropriately differentiate into neurons, or migrate and functionally integrate into the brain. The purpose of this study was to examine a novel strategy for treatment of stroke after injury by optimizing the survival of ischemia-induced endogenous NSCs in the SVZ and SGZ.Methods:Adult SVZ and SGZ NSCs were grown as neurospheres in culture and treated with a p53 inactivator, pifithrin-α (PFT-α), and an amyloid precursor protein (APP)-lowering drug, posiphen, and effects on neurosphere number, size and neuronal differentiation were evaluated. This combined sequential treatment approach was then evaluated in mice challenged with middle cerebral artery occlusion (MCAo). Locomotor behavior and cognition were evaluated at 4 weeks, and the number of new surviving neurons was quantified in nestin creERT2-YFP mice.Results:PFT-α and posiphen enhanced the self-renewal, proliferation rate and neuronal differentiation of adult SVZ and SGZ NSCs in culture. Their sequential combination in mice challenged with MCAo-induced stroke mitigated locomotor and cognitive impairments and increased the survival of SVZ and SGZ NSCs cells. PFT-α and the combined posiphen+PFT-α treatment similarly improved locomotion behavior in stroke challenged mice. Notably, however, the combined treatment provided significantly more potent cognitive function enhancement in stroke mice, as compared with PFT-α single treatment.Interpretation:Delayed combined sequential treatment with an inhibitor of p53 dependent apoptosis (PFT-α) and APP synthesis (posiphen) proved able to enhance stroke-induced endogenous neurogenesis and improve the functional recovery in stroke animals. Whereas the combined sequential treatment provided no further improvement in locomotor function, as compared with PFT-α alone treatment, suggesting a potential ceiling in the locomotion behavioral outcome in stroke animals, combined treatment more potently augmented cognitive function recovery after stroke.

The Role of Hypoxia on the Neuronal Differentiation of Gingival Mesenchymal Stem Cells: A Transcriptional Study

“…Different strategies have been developed in order to promote neurogenesis and regeneration 27,28 . Moreover, in the field of stem cell therapy, the preconditioning of MSCs, culturing them in specific conditions or through the addition of different compounds, may improve their efficacy.…”

GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke

“…Due to the disrupted nerve tracts, the motor and sensory dysfunction persisted for at least 28 days after the stroke. Previous studies have shown the therapeutic effect of endogenous NSCs on MCAO model [ 28 ]. However, no in situ or migrated endogenous NSCs were found in or around the infarct in the brainstem stroke.…”

Inhibition of CSPG receptor PTPσ promotes migration of newly born neuroblasts, axonal sprouting, and recovery from stroke

“…Quantification of brain atrophy in stroke animals using Giemsa staining 4 weeks post stroke, brains were harvested and subjected to Giemsa staining as described previously (Turcato et al, 2018). Briefly, post-stroke 4-week brain sections (25 mm) were mounted on PLL-coated slides.…”