Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats

Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5 μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12 h, 24 h and 72 h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

► Nerve Growth Factor attenuates the edema induced by traumatic brain injury in rats.
► Nerve Growth Factor reduces the expression of aquaporins-4 in the brain of rats.
► Nerve Growth Factor inhibits the activation of NF-kappa B and neuroinflammation.
► The decrease of the neuroinflammation may involve in the reduction of AQP4.
► Our observation provides novel insights on the protective effect of NGF in TBI.