Neurogenesis After Traumatic Brain Injury

Despite improving rates of survival after trau-matic brain injury (TBI), many head-injuredpatients incur permanent neurologic impairment.Each year in the United States, approximately80,000 individuals sustain TBI that results insignificant long-term disability [1]. In addition tolocal neuronal destruction resulting from the pri-mary insult, mechanical brain injury secondarilyinduces a progressive cascade of related eventsthat contribute to neuronal death, including ische-mia, brain edema, diffuse axonal injury, excitotox-icity, radical-mediated damage, mitochondrialdysfunction, and dysregulation of calcium homeo-stasis [2,3]. Despite an improved understanding ofthe pathophysiology that occurs in TBI, clinicalneuroprotection trials pharmacologically target-ing these secondary mechanisms have failed toshow consistent improvement in outcome forhead-injured patients [4]. With the confirmationof continual neurogenesis in the adult human hip-pocampus [5] and subventricular zone (SVZ) [6,7],experimental paradigms have expanded to evalu-ate the response of endogenous neuronal progen-itor cells (NPCs) to traumatic injury. Recentstudies have begun to assess the potential of thesecells to generate new neurons capable offunctionally counterbalancing neuronal loss inTBI. Although this is a lofty goal with numerouspitfalls, accumulating data suggest that neurogen-esis increases in response to mechanical brain in-jury in multiple areas of the adult mammalianbrain. This review aims to summarize these find-ings and to evaluate current progress toward po-tential neurogenesis-targeted clinical therapy.Neuronal loss in traumatic brain injuryNeuronal loss after TBI is focal and diffuse.Focal damage typically involves hemorrhagiclesions within the gray matter or at gray-whitejunctions. These contusions are typically observedat the frontal poles, orbital frontal lobes, temporalpoles, and cortex above the Sylvian fissure [8].Within contusions and adjacent neocortex ofTBI patients, focal neuronal death occurs by ne-crotic and apoptotic mechanisms [9,10]. Amongdiffuse injury sites, the hippocampus is known tobe damaged frequently in human beings, with neu-ronal loss occurring in greater than 80% of fatalTBI, even in the absence of elevated intracranialpressure (ICP) [11,12]. Additionally, apoptoticneurons have been observed in the human hippo-campus up to 12 months after injury [13]. In fact,in the period after the acute phase of focalneuronal injury, hippocampal neurons may bethe most vulnerable neurons in the brain becausethey show the earliest evidence of TBI-induceddegeneration in experimental models [14]. In thetwo most relevant and frequently used experi-mental models of TBI, the lateral fluid percussion(LFP) and controlled cortical impact (CCI) injury