A Feasibility Research On Restoration Of Demyelination In Trigeminal Nerve With Transnasal Administration Of BDNF/NGF Loading On PEG-PLA Nanoparticles

Background.Primary trigeminal neuralgia(TN)is caused by vascular compression of the trigeminal nerve root and the pathology of demyelination has been observed.Although microvascular decompression(MVD)surgery has became the most reasonable technique for this disease,this sort of operation is with risk and invasive.Accordingly,we attempt to find a non-invasive approach to treat TN.Methods.Sprague Dawley(SD)rats were used for the experimental series.The brain-derived neurotrophic factor(BDNF)and nerve growth factor(NGF)were used to restore the myelin sheath of trigeminal nerve,which were loading on poly(ethylene glycol)-poly(lactic acid)(PEG-PLA)nanoparticles firstly.After nasal administration,then the nanoparticles were tracked with a vitro imaging system.The TN model was established by chronic constriction injury of the infraorbital nerve.These rats which only underwent exposure of infraorbital nerve without ligation served as group Sham.Then all the animals would measure the mechanical allodynia,the mechanical testing procedure was modified from previous described Up and Down method by Dixon.Those rats who suffered a obvious decrease of the threshold value were thought as the success animal model and allocated to group TN,group TN+BDNF and group TN+NGF randomly.After administration of BDNF-NPs and NGF-NPs as well as normal saline in different groups,then the mechanical allodynia of these rats were tested again.Finally,the trigeminal nerve specimen were removed for the experiments of electron microscopy,HE-staining,Western-Blotting,RT-PCR,culture of schwann cell,CCK8 assay and immunostaining of S-100.Results.The synthesized BDNF-NPs/NGF-NPs has a mean diameter and encapsulation efficiency of 129.8nm/128.6nm and 83.9%/79.5%with a release rate of 87.6%/85.3%(7 days later),respectively.The fluorescence signals of the nanoparticles appeared in the trigeminal nerve as early as 5 min,became the strongest at 30 min and then became to more and more weaker.A totally of 100SD rats were suffered the chronic constriction injury of the infraorbital nerve.62rats were suffered a obvious decrease of the threshold value and were randomly allocated to group TN(n=22),group TN+BDNF(n=20)and group TN+NGF(n=20).19 of the rats were allocated to group sham.Three weeks after the nasal administration,the mechanical allodynia didn’t change apparently in group Sham and group TN,while it significantly increased in group TN+BDNF and group TN+NGF.The microscopy exhibited that intact myelins with homogeneous density of axon in group TN+BDNF and group TN+NGF as well as in group Sham,while the axons and myelin sheaths were absent in group TN.The results of Western-Blotting and RT-PCR indicated that the level of Na_v1.8 and Bax were significantly increased in group TN compared with other groups(p<0.05).But the level of Bcl-2 and NF-κB were significantly increased in group TN+BDNF and group TN+NGF compared with group TN(p<0.05).The CCK-8 and immunostaining of S-100 experiments indicated that the BDNF-NPs or NGF-NPs could promote the expression of schwann cells(p<0.05).Conclusions.The study demonstrated that BDNF/NGF loading on nanoparticles may transmit along with the trigeminal nerve via nasal administration and facilitate the restoration of myelin sheath.It could be a sort of non-invasive therapeutic method for primary trigeminal neuralgia in the future.