http://www.karplab.net/papers/Mesenchymal_Stem_Cell_Homing___The_Devil_Is_In_The_Details.pdf

Mesenchymal Stem Cell Homing: The Devil Is in the Details

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.

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Animal models of traumatic brain injury

Summary Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.

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Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic

Stroke is associated with a limited degree of functional recovery. Imaging studies in humans have shown that reorganization in periinfarct and connected cortical areas most closely correlates with functional recovery after stroke. On a cellular level, two major regenerative events occur in periinfarct cortex: axons sprout new connections and establish novel projection patterns, and newly born immature neurons migrate into periinfarct cortex. Stroke induces a unique microenvironment for axonal sprouting in periinfarct cortex, in which growth-inhibitory molecules are reduced for 1 month after the infarct. During this period, neurons activate growth-promoting genes in successive waves. Neurogenesis also occurs through waves of migration of immature neurons from their origin in the subventricular zone into periinfarct cortex. This migration is mediated, in part, by the cytokine erythropoietin. These data indicate that the cellular environment after stroke is far from one of just death and destruction, but rather involves a longer evolving process of neuronal regeneration. Poststroke neuronal regeneration is characterized by waves of specific cellular and molecular events. Manipulating these waves of regeneration may provide for novel therapies that will improve recovery after stroke.

Cellular and molecular mechanisms of neural repair after stroke: making waves.

In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.

/pdf/sildenafil-from-angina-to-erectile-dysfunction-to-pulmonary-2r675x6yny.pdf

Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.

Background and Purpose— Erythropoietin (EPO) promotes proliferation and differentiation of erythroid progenitors and the survival of maturing erythroid cells. Here, we investigated the role of EPO in brain repair after stroke. Methods— Rats were treated with recombinant human EPO (rhEPO) at 24 hours after the onset of embolic stroke. An array of behavior tests was performed. Rats were euthanized 28 days after stroke for measurements of infarct volume, angiogenesis, and neurogenesis. In vitro, neurospheres derived from the subventricular zone (SVZ) of the rat and cerebral endothelial cells derived from the mouse were treated with rhEPO. Capillary-like tube formation and neuronal differentiation were measured. Results— Treatment with rhEPO significantly improved functional recovery, along with increases in density of cerebral microvessels at the stroke boundary and numbers of BrdU, doublecortin, and nestin immunoreactive cells in the SVZ. rhEPO treatment significantly increased brain levels of vascular endo...

Treatment of Stroke With Erythropoietin Enhances Neurogenesis and Angiogenesis and Improves Neurological Function in Rats

Background and Purpose— We tested the hypothesis that sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, promotes functional recovery and neurogenesis after stroke. Methods— Male Wistar rats were subjected to embolic middle cerebral artery occlusion. Sildenafil (Viagra) was administered orally for 7 consecutive days starting 2 or 24 hours after stroke onset at doses of 2 or 5 mg/kg per day. Ischemic rats administered the same volume of tap water were used as a control group. Functional outcome tests (foot-fault, adhesive removal) were performed. Rats were killed 28 days after stroke for analysis of infarct volume and newly generated cells within the subventricular zone and the dentate gyrus. Brain cGMP levels, expression of PDE5, and localized cerebral blood flow were measured in additional rats. Results— Treatment with sildenafil significantly (P<0.05) enhanced neurological recovery in all tests performed. There was no significant difference of infarct volume among the experimental groups. Treatmen...

Sildenafil (Viagra) Induces Neurogenesis and Promotes Functional Recovery After Stroke in Rats

We investigated the effects of NO on angiogenesis and the synthesis of vascular endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in the rat. Compared with control rats, systemic administration of an NO donor, DETANONOate, to rats 24 hours after stroke significantly enlarged vascular perimeters and increased the number of proliferated cerebral endothelial cells and the numbers of newly generated vessels in the ischemic boundary regions, as evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with DETANONOate significantly increased VEGF levels in the ischemic boundary regions as measured by ELISA. A capillary-like tube formation assay was used to investigate whether DETANONOate increases angiogenesis in ischemic brain via activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a n...

Nitric Oxide Enhances Angiogenesis via the Synthesis of Vascular Endothelial Growth Factor and cGMP After Stroke in the Rat

Background and Purpose—We tested the hypothesis that intravenous infusion of bone marrow derived–marrow stromal cells (MSCs) enter the brain and reduce neurological functional deficits after stroke in rats. Methods—Rats (n=32) were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Test groups consisted of MCAO alone (group 1, n=6); intravenous infusion of 1×106 MSCs at 24 hours after MCAO (group 2, n=6); or infusion of 3×106 MSCs (group 3, n=7). Rats in groups 1 to 3 were euthanized at 14 days after MCAO. Group 4 consisted of MCAO alone (n=6) and group 5, intravenous infusion of 3×106 MSCs at 7 days after MCAO (n=7). Rats in groups 4 and 5 were euthanized at 35 days after MCAO. For cellular identification, MSCs were prelabeled with bromodeoxyuridine. Behavioral tests (rotarod, adhesive-removal, and modified Neurological Severity Score [NSS]) were performed before and at 1, 7, 14, 21, 28, and 35 days after MCAO. Immunohistochemistry was used to identify MSCs or cells derived from MSCs in bra...

Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats

Background and Purpose—Erythropoietin (EPO), a hematopoietic cytokine, exerts neuroprotective effects in experimental stroke. In the present study, we investigated the effect of recombinant human EPO (rhEPO) in combination with tissue plasminogen activator (tPA) on embolic stroke. Methods—Rats subjected to embolic middle cerebral artery occlusion (MCAO) were treated with rhEPO (5000 U/kg) in combination with tPA (10 mg/kg) at 2 or 6 hours after MCAO. Control groups consisted of ischemic rats treated with rhEPO (5000 U/kg) alone, tPA (10 mg/kg) alone, or saline at 2 or 6 hours after MCAO. Results—The combination therapy of rhEPO and tPA initiated 6 hours after MCAO did not reduce the ischemic lesion volume and significantly (P<0.05) increased the incidence of brain hemorrhage measured by frequency of gross hemorrhage and a quantitative spectrophotometric hemoglobin assay compared with rats treated with rhEPO alone and tPA alone. However, when the combination therapy was initiated 2 hours after MCAO, the tr...

ZhenggangZhang

Papers

Treatment of Stroke With Erythropoietin Enhances Neurogenesis and Angiogenesis and Improves Neurological Function in Rats

Sildenafil (Viagra) Induces Neurogenesis and Promotes Functional Recovery After Stroke in Rats

Nitric Oxide Enhances Angiogenesis via the Synthesis of Vascular Endothelial Growth Factor and cGMP After Stroke in the Rat

Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats

Erythropoietin in Combination of Tissue Plasminogen Activator Exacerbates Brain Hemorrhage When Treatment Is Initiated 6 Hours After Stroke