Scorpion venom heat-resistant peptide(SVHRP)is a component purified from Buthus martensii Karsch scorpion venom.Although scorpions and their venom have been used in Traditional Chinese Medicine to treat chronic neurological disorders,the underlying mechanisms of these treatments remain unknown.We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms.SVHRP administration increased the number of BrdU-positive cells,BrdUpositive/neuron-specific nuclear protein(NeuN)-positive neurons,and polysialylated-neural cell adhesion molecule(PSA-NCAM)-positive immature neurons in the subventricular zone(SVZ)and subgranular zone(SGZ)of hippocampus.However,SVHRP did not promote the proliferation and differentiation of neural stem cells(NSCs)in SVZ and SGZ in vitro and also have no effect on neuronal maturation.But immature neurons incubated with SVHRP-pretreated astrocyteconditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium.This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ,SVZ and olfactory bulb(OB)in the adult mouse brain.In contrast to normal astrocyte-conditioned medium,higher concentrations of brain-derived neurotrophic factor(BDNF)but not nerve growth factor(NGF)or glial cell line-derived neurotrophic factor(GDNF)was detected in the conditioned medium of SVHRP-pretreated astrocytes,and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects.In SVHRP treated mouse brain,more glial fibrillary acidic protein(GFAP)-positive cells were detected.Furthermore,immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells,which agrees with the observed changes in the culture system.Further study,we found that SVHRP could promote the proliferation and differentiation of NSCs from the reprogram of type Ⅱ astrocyte by upregulating transcription factors of Sox2,Oct4,c-Myc and Klf4 in vitro.Its mechanism might be through the PI3K/Akt pathway.These results describe novel effects of scorpion venom-originated peptide on the stem cells and suggest the potential therapeutic values of SVHRP.