The role of neurotensin in preventing neuronal death following peripheral nerve injury

Abstract

Traumatic nerve injury frequently leads to loss of function due to neuronal degeneration and death. The molecular mechanisms involved in neuronal death are poorly understood, but are thought to parallel apoptosis, or programmed cell death. Several molecules have recently been identified as key players in the induction of neuronal death. Sortilin, a recently discovered receptor expressed in neuronal tissues, has been shown to interact with the p75 neurotrophin receptor (p75NTR) in the induction of apoptosis upon binding unprocessed nerve growth factor, also known as proNGF (Nykjaer et al., 2004). Sortilin also functions as a receptor for the peptide neurotransmitter neurotensin. Neurotensin occupies the sortilin receptor and thereby prevents the proNGF-induced formation of the sortilin-p75NTR receptor complex. Therefore, proNGF-activation of the p75NTR apoptotic signaling cascade can be prevented by neurotensin. We sought to determine if the absence of neurotensin in vivo would result in significantly greater neuronal death following peripheral nerve injury. To test this hypothesis, we assessed neuronal survival in L4/5 dorsal root ganglia (DRG) seven days following sciatic nerve transection amongst neurotensin null-mutant (NT -/-), heterozygous (NT+/-), or wild-type (NT +/+) mice (Dr. Paul Dobner, University of Massachusetts Medical Center). We found that in response to peripheral nerve injury, NT-/- mice experience the most dramatic neuronal loss (53%), while NT+/- and NT+/+ mice also suffer a significant neuronal loss of 38% and 26%, respectively. Unexpectedly, exogenous delivery of either 10 μg or 100 μg of neurotensin (7 intrathecal injections total/24-hour cycles) did not prevent DRG neuronal death amongst NT-/- mice after nerve injury. However, NT+/+ mice which received either 10 μg or 100 μg of neurotensin had 61% and 67% more neurons than control mice after injury, respectively. These differential effects produced amongst null-mutant and wild-type mice raise important questions of how neurotensin mediates pro-survival effects. Overall, these data suggest an important role for neurotensin in promoting survival amongst sensory neurons after peripheral nerve injury.