Cerebral ischemia and trauma—different etiologies yet similar mechanisms: neuroprotective opportunities

Abstract

Cerebral ischemia leads to brain damage caused by pathogenetic mechanisms that are also activated by neurotrauma. These mechanisms include among others excitotoxicity, over production of free radicals, inflammation and apoptosis. Furthermore, cerebral ischemia and trauma both trigger similar auto-protective mechanisms including the production of heat shock proteins, anti-inflammatory cytokines and endogenous antioxidants. Neuroprotective therapy aims at minimizing the activation of toxic pathways and at enhancing the activity of endogenous neuroprotective mechanisms. The similarities in the damage-producing and endogenous auto-protective mechanisms may imply that neuroprotective compounds found to be active against one of these conditions may indeed be also protective in the other. This review summarizes the pathogenetic events of ischemic and traumatic brain injury and reviews the neuroprotective strategies employed thus far in each of these conditions with a special emphasize on their clinical relevance and on future directions in the field of neuronal protection.

Introduction

Cerebral ischemia may result from a variety of causes that impair cerebral blood flow (CBF) and lead to deprivation of both oxygen and glucose. When persistent and critical, such impairment in blood flow may eventually lead to neuronal death [6], [12], [123], [127]. Cells at the center of the ischemic focus, the ischemic core, are especially vulnerable and may die within minutes of ischemic onset [123]. The ischemic penumbra surrounding the core is an area of reduced perfusion in which cells are still viable [6], [12], [14], [121], [134], [222]. However, cells in the ischemic penumbra are subjected to various pathological processes that may lead to their demise and their survival is only possible for a limited time [53], [79], [110], [122], [134]. Spontaneous reperfusion usually occurs in the set-up of cerebral ischemia [129]. While this process may reverse the ischemic damage when occurring early enough (e.g., transient ischemic attacks), it usually takes place at a much later time point when most penumbral cells have died.

Traumatic brain injury (TBI), on the other hand, involves a primary mechanical impact that usually causes skull fracture and abruptly disrupts the brain parenchyma with shearing and tearing of blood vessels and brain tissue [88], [207]. This, in turn, triggers a cascade of events characterized by activation of molecular and cellular responses that lead to secondary injury. The evolution of such secondary damage is an active process in which many biochemical pathways are involved (for a review, see Ref. [133]).

Many similarities between the harmful pathways that lead to secondary cellular death in the penumbral ischemic zone and in the area exposed to secondary post-traumatic injury have been identified. In addition, early ischemic episodes are reported to occur after traumatic brain injury, adding a component of ischemia to the primary mechanical damage.

The similar neurochemical milieu around the ischemic core and the site of trauma, along with similar altered gene transcription suggest that similar neuroprotective strategies [171], aimed at interference with harmful mechanisms should be effective in both types of brain injury. The goal of such therapy in both types of injury is to minimize activation of toxic pathways and to enhance activity of endogenous neuroprotective mechanisms as the balance between these pathways will eventually determine the fate of the tissue at risk. Indeed, most neuroprotectants found to be effective in models of experimental stroke are also effective in models of experimental TBI. In summary, it appears that the common pathological and protective processes active in both disorders, as well as the common response to neuroprotective strategies suggest that similar drugs that could be effective against both processes should be developed by scientists active in both fields despite the different etiologies of stroke and trauma.