An additional avenue of research has been focusing on the terminal complement pathway, or "membrane attack" pathway, which results in cellular lysis by the MAC/C5b-9 [51, 84, 85] . In clinical studies, elevated levels of activated soluble MAC/C5b-9 were detected in the CSF of severely head-injured patients [62] . Moreover, the extent of intrathecal complement activation was associated with secondary cerebral insults in TBI patients, including post-injury BBB dysfunction [10, 62, 64] . Experimental studies have revealed that the intracerebroventricular injection of MAC induced a marked upregulation of adhesion molecule expression and leukocyte infiltration in the subarachnoid space and cerebral parenchyma [84] . In addition, MAC injection into hippocampus evoked seizures and neurocytoxic effects in rats [85] . Local MAC deposition in the injured brain was demonstrated in experimental models [86] and in injured human brains [87] . The complement regulatory molecule CD59 represents the main controlling molecule of MAC formation and an essential protector from neuronal cell injury after complement activation [51, 88] . Neurons express CD59 constitutively, as a protective mechanism from autologous "innocent bystander" cell lysis after complement activation in the brain [51, 89] . However, the posttraumatic activation of phosphatidyl-inositol-specific phospholipase C (PI-PLC) after traumatic brain injury renders neurons vulnerable to MAC-mediated lysis by shedding of the glycosyl-phosphatidyl-inositol (GPI)-anchored glycoprotein CD59 from neuronal membranes [88, 90] . A recent experimental study on closed head injury in mice lacking the gene for Cd59a (CD59a -/-) revealed increased susceptibility to brain injury in CD59a -/mice, compared to wild-type littermates [88] . In fact, head-injured CD59a -/mice showed increased neuronal cell death in tissue sections assessed by TUNEL histochemistry, in conjunction with elevated serum levels of neuron specific enolase (NSE), an indirect marker of neuronal injury [88] . These data corroborate the crucial role of the complement regulatory molecule CD59 in protecting neurons from complement-mediated lysis, and emphasize the impact of the terminal complement pathway in contributing to the pathophysiology of delayed neuronal cell death after TBI.