Study About Potential Mechanism Of Intranasal Nerve Growth Factor Improving The Prognosis After Traumatic Brain Injury In Rats

Traumatic brain injury (TBI) is the major cause of the neurological deficit. The pathological response following TBI consists of the primary and secondary injury. Secondary injury, including brain edema and Alzheimer’s disease, is dramatically response to the worse prognosis of patients. Due to the poor blood-brain barrier permeability and peripheral adverse effects, the clinical application of nerve growth factor (NGF) in TBI is limited, though studies showed NGF could improve the prognosis of rats after TBI. Intranasal delivery as a noninvasive and convenient method was successfully target therapeutics to the central nervous system, bypassing the BBB and minimizing systemic exposure. This research was aimed to study the potential mechanism of intranasal NGF improving the prognosis of TBI rats. The Sprague-Dawley male rats were divided to TBI group, NGF+TBI group and control group. We used a modification of the Feeney’s weight-drop model. Rats in NGF+TBI group were administrated with NGF intranasally (50ul/d), and those in TBI group received only phosphate buffer saline (50ul/d). We found that intranasal administration of NGF attenuated the brain edema, as assayed by cerebral water content after TBI. This attenuation was associated with a prominent decrease of the content of aquaporin-4 (AQP4), which was detected by western blotting and immunostaining. By using western blotting and immunostaining, we observed that phosphorylation of tau was increased after TBI. After treatment of NGF, the phosphorylation of tau was decreased. This decrease was related to the inhibition of glycogen synthase kinase-3β (GSK-3β). The two effects mentioned above were associated with the low level of interleukin-1β (IL-1β) by administration of NGF, which were detected by ELISA and qRT-PCR. Moreover, the result of EMSA implied that the DNA binding activity of nuclear factor-κB (NF-κB) was down-regulated in NGF+TBI, which was due to the increasing of B-celllymphoma-2 (Bcl-2) and decreasing of cysteinyl aspartate specific proteinase-3 (caspase-3) by NGF, as evaluated by qRT-PCR. Thus, intranasal NGF improved the prognosis of TBI rats by ameliorating brain edema due to AQP4 and tau phosphorylation related to GSK-3β. The further research exhibited that those effects were associated with attenuation of neuroinflammation regulated by Bcl-2/caspase-3/NF-κB.