Endogenous Agents That Contribute to Generate or Prevent Ischemic Damage

From single to multicellular organisms, protective mechanisms have evolved against endogenous and exogenous noxious stimuli. Over the past decades numerous signaling pathways by which the brain senses and reacts to such insults as neurotoxins, substrate deprivation and inflammation have been discovered. Research on preconditioning is aimed at understanding endogenous neuroprotection to boost it or to supplement its effectors therapeutically once damage to the brain has occurred, such as after stroke or brain trauma. Another goal of establishing preconditioning protocols is to induce endogenous neuroprotection in anticipation of incipient brain damage. Currently several endogenous neuroprotectants are being investigated in controlled clinical trials. There is consensus that many of the neuroprotectants, which were highly effective in animal models of stroke, but failed in clinical trials, were unsuccessful because of side effects, which in many cases led to premature termination of the trial. Nowadays research aims to overcome this problem by developing compounds which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. In the present review we will give a short overview on the signals, sensors, transducers, and effectors of endogenous neuroprotection. We will first focus on common mechanisms, on which pathways of endogenous neuroprotection converge. We will then discuss various applications of endogenous neuroprotectors and explore the prospects of endogenous neuroprotective therapeutic approaches.