Barone FC, Feuerstein GZInflammatory mediators and stroke: New opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819-834

Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 09/1999; 19(8):819-34. DOI: 10.1097/00004647-199908000-00001
Source: PubMed


Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide "neuroprotection" in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-alpha, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.

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    • "The motor functional benefit, however, was more persistent in mESC transplantation, showing much better performance than control animals at 28 days after MCAO. More long-term investigation may be needed to verify the persistence of the morphological and functional benefits of the transplantation strategy (Barone and Feuerstein, 1999). Our finding showed that the infarct size was significantly reduced in both cell-transplanted groups and the post-ischemic exercise group, compared with the sham-operated group. "
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    ABSTRACT: We induced middle cerebral artery occlusion (MCAO) in rats using silicone-coated vascular embolus. We transplanted mouse embryonic stem (mES) cells after MCAO. Rats were tested behaviorally using motor and sensory function with neurological assessment. Functional effectiveness of the transplanted mES cells gradually improved the function of sensory and motor neurons. This study demonstrated that the transplanted cells have synaptic connection in the recipient brain. We suggest that stem cell transplantation can have a positive effect on behavioral recovery and reduction of infarct size in focal ischemic rats. Cell transplantation may induce certain functional recovery of the brain tissue by endogenous cell mediated effect. Our study suggests that intracerebrally injected mES cells survived and migrated into the infarct area from inoculation site and neuroglially differentiated in the ischemic brain area of adult rats. Therefore, mES cells may be a useful tool for the treatment in neurological diseases. In conclusion, cell transplantation therapy represents a novel approach that may enhance the efficacy and effectiveness of stem cell transplantation after ischemic stroke.
    Full-text · Article · Jun 2015
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    • "Increasing evidence suggests that inflammatory cytokines with activated macrophages are detrimental to neural cells. Inflammatory mechanisms appear to be the key factors in secondary brain injury, such as neuronal-cell death and reactive gliosis after intracerebral hemorrhaging29,30,31). A study involving the newborn rabbit IVH model showed that the inhibition of cycloxygenase-2 in the inflammatory cascade, which is induced by IVH, alleviated neurological impairment and delayed myelination and reactive gliosis32). "
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    ABSTRACT: Severe intraventricular hemorrhaging (IVH) in premature infants and subsequent posthemorrhagic hydrocephalus (PHH) causes significant mortality and life-long neurological complications, including seizures, cerebral palsy, and developmental retardation. However, there are currently no effective therapies for neonatal IVH. The pathogenesis of PHH has been mainly explained by inflammation within the subarachnoid spaces due to the hemolysis of extravasated blood after IVH. Obliterative arachnoiditis, induced by inflammatory responses, impairs cerebrospinal fluid (CSF) resorption and subsequently leads to the development of PHH with ensuing brain damage. Increasing evidence has demonstrated potent immunomodulating abilities of mesenchymal stem cells (MSCs) in various brain injury models. Recent reports of MSC transplantation in an IVH model of newborn rats demonstrated that intraventricular transplantation of MSCs downregulated the inflammatory cytokines in CSF and attenuated progressive PHH. In addition, MSC transplantation mitigated the brain damages that ensue after IVH and PHH, including reactive gliosis, cell death, delayed myelination, and impaired behavioral functions. These findings suggest that MSCs are promising therapeutic agents for neuroprotection in preterm infants with severe IVH.
    Full-text · Article · Jun 2014 · Korean Journal of Pediatrics
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    • "One of the most prevalent neurological disorders in which excitotoxicity is involved is stroke, including ischemic stroke and brain hemorrhage [39]. In stroke, the initial ischemic or hemorrhagic brain damage is usually followed by more delayed secondary brain damage that is characterized by microglial and astrocyte activation, induction of inflammatory and potentially neurotoxic mediators, and leukocyte infiltration [40, 41, 42, 43, 44]. The concerted effects of these inflammatory events result in delayed neuronal death leading to further sustained and aggravated neurological damage subsequent to the stroke. "
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    ABSTRACT: Toll-like receptors (TLRs) belong to a class of pattern recognition receptors that play an important role in host defense against pathogens. TLRs on innate immune cells recognize a wide variety of pathogen-associated molecular patterns (PAMPs) and trigger innate immune responses. Later, it was revealed that the same receptors are also utilized to detect tissue damage to trigger inflammatory responses in the context of non-infectious inflammation. In the nervous system, different members of the TLR family are expressed on glial cells including astrocytes, microglia, oligodendrocytes, and Schwann cells, implicating their putative role in innate/inflammatory responses in the nervous system. In this regard, we have investigated the function of TLRs in neuroinflammation. We discovered that a specific member of the TLR family, namely TLR2, functions as a master sentry receptor to detect neuronal cell death and tissue damage in many different neurological conditions including nerve transection injury, intracerebral hemorrhage, traumatic brain injury, and hippocampal excitotoxicity. In this review, we have summarized our research for the last decade on the role of TLR2 in neuroinflammation in the above neurological disorders. Our data suggest that TLR2 can be an efficient target to regulate unwanted inflammatory response in these neurological conditions.
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