Inhibition of mannose binding lectin is protective in experimental traumatic brain injury

AIMS We have previously demonstrated the presence of mannose binding lectin (MBL) in the brain of traumatic brain injured (TBI) patients and in that of mice subjected to experimental TBI, where MBL-C exceeds MBL-A. We have also shown that the susceptibility to TBI is significantly reduced in MBL double knock-out compared to wild type mice at 2-5 weeks postinjury (1). We have now evaluated the effect of the administration of two multivalent glycomimetic MBL-ligands, Polyman-2 (2) and Polyman-9, on mouse TBI progression. METHODS and RESULTS Polyman-2 and Polyman-9 were selected for their interaction with MBL-A and MBL-C, evaluated by surface plasmon resonance (SPR). Polyman-2 showed higher binding to MBL-A, while Polyman-9 showed a similar binding to MBL-A and MBL-C. Furthermore, Polyman-9 binding to MBL-C was higher than that of Polyman-2. Male C57Bl/6 mice were subjected to sham or controlled cortical impact brain injury (parameters: velocity 5 meter/sec and depth 1 mm). At 10 minutes postinjury, mice randomly received an intravenous infusion of either Polyman-2, Polyman-9 or saline. Functional outcome was evaluated using the neuroscore and beam walk tests weekly, up to 4 weeks postinjury. Brain-injured mice receiving saline or Polyman-2 had similar neurobehavioral deficits. On the contrary, brain-injured mice receiving Polyman-9 had significantly reduced sensorimotor deficits compared to saline treated mice at 2-4 weeks postinjury. CONCLUSIONS Differently from Polyman-2, Polyman-9 confers neurobehavioural protection after TBI. This effect may be due to Polyman-9 higher affinity to MBL-C. Together with the decreased response to TBI reported in MBL KO mice, these data demonstrate the MBL relevance in TBI setting. 1) Longhi L, Orsini F, De Blasio D, Fumagalli S, Ortolano F, Locatelli M, Stocchetti N, De Simoni M G, Mannose binding lectin expressed after clinical and experimental traumatic brain injury and its deletion is protective. Critical Care Medicine 2014, in press 2) Orsini F, Villa P, Parrella S, Zangari R, Zanier E, Gesuete R, Stravalaci M, Ottria R, Reina JJ, Paladini A, Micotti E,Ribeiro-Viana R, Rojo J, Pavlov VI, Stahl GL, Bernardi A, Gobbi M, and De Simoni MG. Targeting mannose binding lectin confers long lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. Circulation 2012; 126: 1484-1494.