Neuroprotective interventions

At this time, however, we are not aware of any compounds selected primarily by their neuroprotection activity on rodent models that have established clinical efficacy for dementias or related neurodegenerative diseases. This may be partially explained by their priority development for stroke, and clinicians have found it is difficult or unlikely to slow the ischemia in patients if they are not treated aggressively within 3 h of the initial ischemic event. The speed of neurodegeneration in stroke (cerebral ischemia) makes it a much more difficult target for drug intervention than neurodegeneration from slower pathologies such as Alzheimer s, Parkinson s, and malfunctions in neurotransmitters. 

The usual definition of a neuroprotectant is an agent that aims to prevent neuronal death by inhibiting one or more of the pathophysiological steps in the processes that follow injury to the central nervous system (CNS) or ischemia due to occlusion of an artery or hypoxia due to any cause. This definition has now been extended to include protection against neurodegeneration and neurotoxins. The extended definition includes interventions that slows or halts the progression of neuronal degeneration. 

By using a thresholding approach in a 3-D CBF data set, we could show that 54% of the total ischemic lesion volume could be attributed to the penumbra, only 46% to the infarct core at 1.5 h post MCA occlusion (Back et al. 1995). Those areas with pending infarction show potentially reversible changes that can be addressed by therapeutic interventions like recanalizing therapy and/or neuroprotective drugs. 

The concept of neuroprotection relies on the fact that delayed neuronal injury occurs after ischemia, and each step along the ischemic cascade provides a target for therapeutic intervention. Thus, understanding the cellular and molecular mechanisms that underlie the development of neuronal and vascular injury is critical to optimize treatment. This chapter reviews experimental evidence from studies on focal cerebral ischemia and mild hypothermia, as well as the mechanisms involved in mild hypothermic neuroprotection. 

It is clear that the closure of voltage-gated K" " charmels by hypoxic exposure has implications for neuroprotection as demonstrated by K+ channel arrest in hypoxia-tolerant turtles (Pek and Lutz, 1997 Bidder and Buck, 1998 Hochachka and Lutz, 2001 Bidder and Donohoe, 2002), which reduces Ca" influx (Bidder and Buck, 1998). In some anoxia-tolerant spedes, neuronal energy is not only conserved by ion channel arrest but also by ATP-sensitive mitochondrial K+ channel arrest (reviewed by Buck and Pamenter, 2006). This may have implications for chnical interventions. 

Manipulation of the tryptophan pathway continues to provide a range of potential therapeutic targets for disease intervention. Inhibition of the KP and the control of excitotoxic and neuroprotective metabolites are of particular interest in the treatment of HD. Although the discovery of a potent and selective inhibitor of the KP capable of efficacy in vivo in animals is challenging, the true hurdle for researchers is the translation of these lead compounds into viable therapies for the treatment and control of HD. 

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