Characterizing the Therapeutic Roles of Depleting Brain-Infiltrated Leukocytes Using Pan-Selectin Antagonist and Intravenous Immunoglobulins in Traumatic Brain Injury

The severely forceful impact on the head, the subsequent dramatic increase in intracranial pressure (ICP) and neuroinflammation usually leads to permanent or long-term disability or even death of patients suffered with traumatic brain injury (TBI). The direct impact on head is referred as the primary injury and high intracranial pressure combined with trauma-induced neuroinflammation is called as the secondary injury. The symptoms of primary injury includes the disruptive brain parenchyma tissue, extensive leakage of brain-blood barrier (BBB) , leading to breed and irreversible damages on neurons in brain. Following the initial impact- or collision-induced primary injury, edema plus numerous proinflammatory mediators including cytokines, growth factors and toxic free radicals released form injured tissues and cells plus the numerous brain-infiltrated leukocytes contribute to form the harmful cytokine storm to deteriorate the functions of neurons in brain, referred as the secondary injury in TBI. During neuroinflammation, those proinflammatory mediators boot more leukocyte recruitments into the injured site of brain passing through the disarrayed blood-brain barrier (BBB). Therefore, TBI-induced cytokine storm or the secondary injury attributes to the irreversible damage in neurons, leading to the elevated rate of mortality and permanent impairments on TBI patients. Therefore, any interventions in blocking newly infiltrated leukocytes into to brain may reduce the degree of cytokine-induced secondary injury and prevent patients from developing long term or permanent brain injury. Moreover, it has been demonstrated that early infiltrated neutrophils play an important role in mediating neuroinflammation-induced cell death. Therefore, we would to hypothesize that blockade of infiltrated leukocytes to brain may effective relieve the symptoms and better prognosis in TBI patients. Our previous study indicated that intravenous immunoglobulins (IVIGs) can inhibit activations and adhesion of neutrophils to postcapillary venules of cremaster muscle in transgenic sickle mice. Furthermore, a pan-selectin antagonist GMI-1070 also reduced adhesions of leukocytes on venules, leading to reverse sickle vasoocclusion in sickle animals. These studies suggest that IVIGs or pan selectin antagonists may block infiltrations or extravasations of leukocytes during TBI. In order to test our hypothesis, we will use IVIG and pan-selectin antagonist GMI-1271 to block the infiltrations of leukocytes to injured brain and then evaluate their therapeutic effects. IVIG are known and commonly used in clinical drug treat patients suffered with certain types of autoimmune diseases and the pan antagonist GMI-1271, a derivative of GMI-1070, has five time more inhibitory activity in leukocyte adhesion. We will first characterize the therapeutic potential of IVIGs and GMI-1271 in TBI animal and then this preclinical data will benefit us to redesign or reform a more effective drug candidates or therapeutic protocol in the future. We will analyze and assess the results from these following studies in this proposal, including ⑴ the IVIG- or GMI-1271- induced alterations in the numbers of the infiltrated leukocytes in injured brain of animals,⑵ the changes or improvements in behavior patterns such as agility, cognition, learning and memory in recovered TBI animals after intervention of IVIGs or GMI-1271, (3) the incidence of TBI-induced organ injuries or failures in lung, kidney and liver, (4) alterations of survival in TBI animals followed with administration of IVIGs or GMI-1271 and potential side effects, (5) illustrations of IVIG- and GMI-1271- induced protective mechanism to TBI.