Exogeneous Brain Derived Neurotrophic Factor Increases Neurogenesis Of Endogenous Neural Stem Cells After Experimental Streptococcous Pneumonia Meninigtis

Objective: Streptococcus pneumonia meningitis acts as a common pediatric infectious disease in nervous system.Despite the effective use of antibiotics,occurrences of mortality and neurological sequelae following Streptococcus pneumonia meningitis remain high and persist throughout adulthood,which affect the quality of life.Brain-derived neurotrophic factor(BDNF)is widely expressed in the adult brain,which could play an important role in the regulation of neuronal development,survival,and cell death.And the application of BDNF could also protect the brain in many neurological diseases.Some study has found that the decreased levels of hippocampal BDNF are related with behavioral deficits following antibiotic treatment in Streptococcus pneumonia meningitis.Meanwhile,hippocampal apoptosis could also impair the normal learning and memory function in hippocampus.Thus,whether BDNF could increase the number of neural cells in the dentate gyrus(DG)of hippocampus by enhancing the neurogenesis of endogenous neural stem cells(NSCs)is unknown at present.In our previous studies,we have found the impaired neurons in cortex and hippocampus and increased expression of BDNF,BDNFm RNA and Trk Bm RNA following the acute Streptococcus pneumonia meningitis,but declined with time past.After antibiotic treatment,down-regulation expression of BDNF,BDNFm RNA and Trk Bm RNA were observed compared with controls.What's more,exogenous BDNF treatment can protect the survival of neurons in the cerebral cortex and hippocampus and hearing loss following Streptococcus pneumonia meningitis.Based on the previous results,our present study aimed to investigate the influence of exogenous infusion of BDNF in regulating the neurogenesis of NSCs in hippocampus DG after experimentally induced Streptococcus pneumonia meningitis with antibiotic treatment in rats.Methods: Three-week-old SD rats were used to construct the models of Streptococcus pneumonia meningitis or control via inoculation of serotype III Streptococcus pneumonia or saline.We randomly divided the rats into four major groups as follows:(1)BDNF-treated meningitis rats,sacrificed on the 7t h day,14 t h day or 28 t h day after inoculation;(2)saline-treated meningitis rats sacrificed on the 7t h day,14 th day or 28 t h day after inoculation;(3)BDNF-treated control rats sacrificed on the 7th day,14 th day or 28 t h day after inoculation;and(4)saline-treated control rats sacrificed on the 7t h day,14 th day or 28 t h day after inoculation.We investigated the neurogenesis of endogenous NSCs after inoculation with exogenous BDNF in the hippocampus dentate gyrus following experimental Streptococcus pneumonia meningitis via immunofluorescence.Double-labeling immunofluorescence with Brd U&Nestin,DCX,Brd U&DCX/Brd U and Brd U&Neu N/Brd U were used to identify newly generated NSCs,immature neurons,the ratio of differentiated immature neurons and mature neurons.Results:(1)After 7 days antibiotic treatment and adjuvant therapy with exogenous BDNF or saline in Streptococcus pneumonia meningitis,we can see the Brd U&Nestin co-expressed NSCs in the DG of hippocampus,characterized with round or oval.The number of Brd U&Nestin co-labeled cells in the BDNF-treated infected rats was also significantly increased in the DG compared among infected rats treated with saline(P=0.001).Moreover,this increased population of Brd U&Nestin coexpression cells was also observed in the control rats treated with BDNF compared with the control rats treated with saline rats(P=0.014).And the number of Brd U&Nestin co-labeled cells was significantly higher in the BDNF-treated infected rats comparing to BDNF-treated control rats(P=0.005)and saline-treated control rats(P=0.000).What's more,increased number of newly generated NSCs was also observed in saline-treated infected rats compared with saline-treated control rats(P=0.029).(2)After 7 days antibiotic treatment and adjuvant therapy with exogenous BDNF or saline,we found a decline in the DG in infected rats treated with saline compared among infected rats treated with BDNF,control rats treated with BDNF and control rats treated with saline(F=7.308,P=0.011).After the treatment of exogenous BDNF,the number of DCX-positive cells in the infected rats was approximately equal to that of the control rats(P>0.05).Compared with control rats treated with saline,there was also a slight increase in control rats treated with BDNF(P>0.05).(3)We found that after BDNF treatment,the percentage of Brd U&DCX/Brd U co-labeled cells increased in infected rats compared with saline-treated infected and control rats 7 days after inoculation(F=18.939,P=0.001).Meanwhile,the ratio of Brd U&DCX/Brd U coexpression cells in BDNF-treated control rats was significantly higher compared to saline-treated infected(P=0.002)and control rats(P=0.000).Fourteen days after inoculation,the percentage of Brd U&DCX/Brd U increased significantly in BDNF-treated infected rats compared with saline-treated infected rats and control rats(F=5.190,P=0.024).Data also showed that,there was no significant difference between control rats in 14-day groups(P>0.05).(4)28 days after infection,we found a few round or oval Brd U&Neu N co-labeled newly neurons located in DG of hippocampus.Although the percentage of Brd U&Neu N/Brd U co-labeled cells was a little higher in infected rats,no significant differences were observed compared with controls(H=2.556,P=0.465).Conclusions:(1)Streptococcus pneumonia meningitis could activate the proliferation of endogenous NSCs but could also impair the early differentiation of endogenous NSCs into immature neurons.(2)Administration of exogenous BDNF may enhance the proliferation and early differentiation of endogenous NSCs in DG of hippocampus,which may play an important role in increasing neurogenesis following Streptococcus pneumonia meningitis.