Neurosurgical procedures can lead to postoperative cerebral damage at the margins of the operative site. This SBI can damage viable brain tissue unintentionally by a wide range of methods used during neurosurgical interventions. The concern with these injuries is the heightened inflammatory response that can propagate direct cell death that, in turn, can enhance BBB disruption, with subsequent increase in brain edema and deterioration in neurobehavioral function. Even if patients survive the insult, currently there are limited effective treatment options to help them recover afterwards. Similarly, effective pretreatment therapies to help prevent and/or reduce SBI damage are also limited. In the present study, we investigated the effects of EAA therapy on SBI, including the potential of this therapy to reduce brain edema and thus prevent the development of sensorimotor behavioral deficits.

Structural brain damage manifesting as cell death and edema following SBI is not an uncommon phenomenon. Previous work in SBI has shown massive neuronal degeneration and death in the area of injury [12], along with findings of increased expression of proapoptotic factors, inflammatory mediators, and proteolytic enzymes throughout the brain and in circulation. Furthermore, BBB integrity can be compromised through matrix metalloproteinase upregulation [2, 9, 15], which leads to propagation of inflammatory cell-mediated cerebral damage and worsening of cerebral edema. One of the orchestrators of BBB disruption is plasmin.

EAA acid is a well-recognized lysine antifibrinolytic analogue. It works primarily by competitively inhibiting the conversion of plasminogen to plasmin in the bloodstream [3]. By doing so, EAA can reduce the levels of active plasmin and potentially preserve the neurovascular unit of the brain. Previous studies in the pediatric extracorporeal membrane oxygenation patient population found that EAA significantly reduced the incidence of intracerebral hemorrhage through BBB preservation, possibly through plasmin inhibition. In the spontaneous intracerebral hemorrhagic stroke population, research suggests that EAA could decrease hematoma sizes in stroke victims by reducing plasmin-mediated neuronal damage [10]. Other studies showed that re-hemorrhage following subarachnoid hemorrhage was significantly reduced, in part because of plasmin inhibition [5, 11]. These studies suggest a role for EAA therapy to block the effects of plasmin on BBB disruption and, in doing so, improve the neurological outcome of subject populations. We found that EAA therapy before surgery resulted in reduced cerebral edema and with the apparent structural protection, neurobehavioral function was well preserved. This is similar to previous work, suggesting that EAA may provide a therapeutic regimen necessary to block plasmin-mediated neurovascular and neurologic damage. Our study had limitations in that we did not study the potential mechanism of EAA-induced reduction in brain edema following SBI. Further studies are warranted to determine how EAA mediates preservation of the neurovascular unit following SBI.