Therapeutic Strategy for Ischemic Stroke
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Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.
KeywordsCerebral ischemia Free radical G-CSF Neural stem cells Scaffold
Free Radical Scavengers
Plenty of free radicals are generated during an ischemic stroke. These can peroxidize lipid, protein, and DNA in various brain cells, and have been implicated in the pathogenesis of cerebral infarction . Thus, free radicals are regarded as an important therapeutic target for improving the outcome of an ischemic stroke. Recent studies using an animal model have reported that brain ischemic injury was ameliorated by using several free radical scavengers such as 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; Trolox , 2,2,5,7,8-pentamethyl-6-hydroxychromane; PMC , disodium 4-[(tert-butylimino)-methyl]benzene-1,3-disulfonate N-oxide; NXY-059 , and 3-methyl-1-phenyl-2-pyrazolin-5-one; MCI-186 . In large clinical trials in human, NXY-059 initially showed a reduction in disability following a stroke (SAINT I) , but eventually failed to represent the initial effect (SAINT II) . In contrast, we originally reported that MCI-186 ameliorated brain edema in the ischemic brain , and has already been applied for a human clinical setting in Japan, and shown the effect of reducing the disability in stroke patients . Recently we have sought new free radical scavengers, especially from preexisting drugs applied for different diseases (e.g., calcium channel blockers (CCBs) for hypertension) or endogenous effectors which humans originally possess (e.g., biliverdin), because these are expected to be applied as clinical drugs in the near future.
Several CCBs have a dihydropyridine ring which can reduce oxidative stress . In order to clarify whether CCBs have an antioxidative property against cerebral ischemia, we treated Wistar rats with a CCB, azelnidipine (1 mg/kg), subjected the rats to 90-min MCAO, and investigated its effects on infarct volume and the oxidative damage. Treatment with azelnizipine reduced infarct volume and brain edema, compared with the vehicle. The expression of oxidative stress markers, such as HEL, 4-HNE, AGE, and 8-OHdG, were significantly decreased in the azelnizipine-treated group. These results suggested that azelnizipine had a neuroprotective effect in the ischemic brain, which came from, at least in part, its anti-oxidative property .
Biliverdin, one of the by-products of heme degradation, is also known to possess a cytoprotective effect against oxidative stress . To estimate the effect of bilverdin on ischemic injury, biliverdin or vehicle was administered intraperioneally after 90-min MCAO. Biliverdin treatment significantly reduced infarct volume of the cerebral cortices. Ethidium staining at 4 h after MCAO revealed that superoxide production in the cerebral cortex was significantly reduced in the biliverdin-treated group. Moreover, biliverdin treatment decreased the number of stained cells for oxidative injury markers, 4-HNE and 8-OHdG. These results indicated that biliverdin-administration ameliorated ischemic brain injury through anti-oxidant mechanism .
The results of previous studies have suggested that the inflammatory reaction plays an important role in contributing to the pathophysiology of ischemia [14, 15, 16]. Thus, we have been interested in inflammatory cytokines such as IL-6  and G-CSF, as effective candidates for neuroprotection.
Stem Cell Therapy
To supply new neurons into the damaged brain after a stroke, two tactics are proposed. One is the activation of intrinsic neural stem cells [20, 21, 22]. The other is the transplantation of extrinsic neural stem cells  (Fig. 1). Recent studies reported the scaffold to be important for intrinsic or extrinsic stem cells to survive in necrotic brain tissue forming a cavity after brain injury [24, 25, 26]. We thus studied scaffolds by providing an appropriate environment to stem cells, and developed new methods using a new porous gelatin–siloxane hybrid derived from the integration of gelatin and 3-(glycidoxypropyl) trimethoxysilane . This porous hybrid implanted into a defective part of the cerebral cortex and maintained at the same site for 60 days retained the integrity of the brain’s shape, and attached well to the surrounding brain tissues. Marginal cavities of the scaffolds remained occupied by newly formed tissue in the brain, where newly produced endothelial, astroglial, and microglial cells were observed with bromodeoxyuridine double positivity. In addition, those cells increased in a dose-dependent manner following the addition of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) [1, 28]. These results suggest that this new porous gelatin–siloxane hybrid has biocompatibility after implantation into a lesion of the central nervous system, and thus provided a potential scaffold for cell migration and angiogenesis with dose-dependent effects following the addition of bFGF and EGF.
In this paper, we briefly highlighted our recent progress in the development of these distinct new strategies for the treatment of damaged brains following a stroke. To realize more effective therapies for patients who have suffered a stroke, it is important to combine these strategies in the acute or chronic phase following a stroke.
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