Mechanism of Neuroprotection in Ischemic Injury

Enzyme/cytoldne/adhesion molecule Effect References 

Secretory PLA2 Upregulation Pizzi et al. (2005), Ftirooqui (2009a) 

Nitric oxide synthase Upregulation Sun et al. (2007), Farooqui (2009a) 

Tumor necrosis factor-a Upregulation Farooqui (2009a) 

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The neuroprotective properties of mild hypothermia have been demonstrated in numerous experimental animal models. Research in this area has been conducted for many years, yet the mechanisms of cerebral protection by mild hypothermia remain unclear and continue to be the subject of intense investigation. The neuroprotective effects of mild hypothermia have been attributed to alterations in metabolic rate (24), neurotransmitter release (25-27), activity of protein kinases (28), resynthesis of cellular repair proteins (29), cerebral blood flow (30), preservation of the blood-brain barrier (BBB) (31), attenuation of inflammatory processes (32,33), and decreases in free radical production (34). Although these may all be components of a complex cascade leading to neurologic injury, it has become increasingly clear that the primary mechanism of action of hypothermia may be different at various temperatures as well as under different ischemic and traumatic conditions. 

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. 

Ziconotide is neuroprotective in rat models of ischemic neuronal damage and after intrathecal administration, antinociception is observed in rats with limited toxicity. The neuroprotective effects observed in rat models are thought to be due to a reduction in body temperature. Analgesic effects are observed in cancer and AIDS patients whose pain was not relieved after opioid administration and in neuropathic conditions. Intrathecal administration of ziconotide prevents mechanical and cold allodynia and heat hyperalgesia " in neuropathic rats. The use of N-type VSCC inhibitors in both ischemic brain injury and pain treatment is complicated by their important role in the synapse. Adverse effects are observed in patients but they are managed through dose reduction or symptomatic treatment, although serious supraspinal and systemic adverse effects have been seen. ... 

Love S (1999) Oxidative stress in brain ischemia. Brain Pathol 9 119-131 Lu A, Tang Y, Ran R, Clark JF, Aronow BJ, Sharp FR (2003) Genomics of the periinfarction cortex after focal cerebral ischemia. J Cereb Blood Flow Metab 23 786-810 Luo Y, Ji X, Ling F, Li W, Zhang F, Cao G, Chen J (2007) Impaired DNA repair via the base-exdsion repair pathway after focal ischemic brain injury a protein phosphorylation-dependent mechanism reversed by hypothermic neuroprotection. Front Biosci 12 1852-1862 Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28 51-65... 

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