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1.  Adenosine kinase is a new therapeutic target to prevent ischemic neuronal death 
The open drug discovery journal  2010;2(3):108-118.
The brain has evolved several endogenous mechanisms to protect itself from the deleterious consequences of stroke. One of those endogenous neuroprotective systems is centered on the purine ribonucleoside adenosine, which exerts potent neuroprotective functions within the brain. One major goal in therapeutic stroke research is to explore and utilize such endogenous neuroprotective mechanisms therapeutically. This review illustrates molecular approaches to study the role of the adenosine system within the context of stroke and highlights innovative therapeutic approaches aimed at increasing adenosinergic function. New research data suggest that the major adenosine regulating enzyme adenosine kinase (ADK) plays a prominent role in determining the brain’s susceptibility to ischemic injury. Thus, endogenous ADK is rapidly downregulated following a stroke, possibly an endogenous neuroprotective mechanism aimed at raising ambient levels of adenosine in brain. Conversely, transgenic overexpression of ADK in brain renders the brain more susceptible to stroke-induced neuronal cell loss. In the present review we will first summarize the physiological role of adenosine metabolism within the context of ischemic brain injury. Next, we will highlight the key role of ADK in determining the brain’s susceptibility to ischemic injury, and finally we will discuss potential therapeutic applications of adenosine augmentation to provide neuroprotection in stroke.
PMCID: PMC3786597  PMID: 24089624
adenosine; adenosine kinase; ischemia; reperfusion; neuroprotection; stroke; transgenic mice; gene knockout
2.  The Protective Effects of Ischemic Postconditioning against Stroke: From Rapid to Delayed and Remote Postconditioning 
The author reviews the protective effects of ischemic postconditioning, a recently emerging strategy with broad implications in the search for new treatments in stroke and myocardial ischemic injury. Ischemic postconditioning, which refers to a series of brief ischemia and reperfusion cycles applied immediately at the site of the ischemic organ after reperfusion, results in reduced infarction in both cerebral and myocardial ischemia. Conventional postconditioning induced within a few minutes after reperfusion is arbitrarily defined as rapid postconditioning. In contrast, postconditioning performed hours to days after stroke is defined as delayed postconditioning. In addition, postconditioning can be mimicked using anesthetics or other pharmacological agents as stimuli to protect against ischemia/reperfusion injury or performed in a distant organ, which is known as remote postconditioning. In this article, the author discusses the conceptual origin of classical rapid ischemic postconditioning and its evolution into a term that represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, and remote postconditioning. Thereafter, various in vivo and in vitro models of postconditioning and its potential protective mechanisms are discussed. Since the concept of postconditioning is so closely associated with that of preconditioning and both share some common protective mechanisms, whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone is also discussed.
doi:10.2174/1877381801002010138
PMCID: PMC3204606  PMID: 22053169
Postconditioning; preconditioning; stroke; cerebral ischemia; focal ischemia; neuroprotection
3.  Targeting Dopamine in Acute Traumatic Brain Injury 
In addition to the initial mechanical damage, traumatic brain injury (TBI) induces a series of secondary insults, such as, but not limited to, excitotoxicity, metabolic disruption, and oxidative stress. Neuroprotective strategies after TBI have traditionally focused on cellular preservation as the measurable endpoint although multiple lines of evidence indicate that even with significant neuronal sparing deficits remain at both the cellular and behavioral level. As such, the development of therapies that can effectively confer both neuronal sparing and post-injury functional benefit is critical to providing the best treatment options for clinical TBI. Targeting dopaminergic signaling pathways is a novel approach in TBI that provides benefits to both neuronal survival and functional outcomes. Dopamine, like glutamate, can cause oxidative stress and significant cellular dysfunction when either depleted or over-expressed, and also plays an important role in central nervous system inflammation. The purpose of this review is to discuss dopamine in acute TBI and the role that dopaminergic therapies have as neuroprotective strategies.
doi:10.2174/1877381801002010119
PMCID: PMC3269831  PMID: 22308176
Dopamine; traumatic brain injury; neuroprotection; plasticity
4.  Estrogen and P2 Purinergic Receptor Systems in Microglia: Therapeutic Targets for Neuroprotection 
Microglia, the primary resident immune cell population in the CNS, react to signals of injury or infection and produce inflammatory cytokines, chemokines, and reactive oxygen species, many of which can be neurotoxic in large quantities. Indeed microglial hyperactivation is thought to contribute to the pathology of many neurodegenerative disorders as well as ischemic and traumatic brain injuries, suggesting that agents with the capacity to target microglial activities may be beneficial for treating neuronal injury. In this review, we discuss two seemingly unrelated microglial receptor signaling systems that potently modulate many microglial properties; purinergic P2 and estrogen receptors. Purinergic receptors regulate key microglial functions, including their production of pro-inflammatory cytokines, neurotrophic factors, migration, phagocytosis and chemotaxis. Many of these same endpoints are also altered by estrogen receptor signaling in microglia. Here we summarize the current microglial research in both receptor areas, particularly as it relates to ischemic and traumatic CNS injuries. We provide evidence from our own laboratory of potential cross-talk between these receptor systems and discuss evidence indicating that both purinergic and estrogen receptors may represent useful therapeutic targets for the treatment of CNS disorders.
doi:10.2174/1877381801002010148
PMCID: PMC3180920  PMID: 21961028

Results 1-4 (4)