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SummaryAims Nerve growth factor (NGF) eyedrops (ed-NGF) activate brain neurons, stimulate growth factors, including brain-derived neurotrophic factor (BDNF), and exert neuroprotection in the forebrain of streptozotocin-induced diabetic rats (STZ rats). In this study, the effects of ed-NGF on BDNF signaling in the prefrontal cortex (PFC) were explored in healthy and STZ-diabetic rats, in which cortical neuronal and axonal loss, and altered circulating BDNF associated with depressive phenotype are also described. Methods STZ and healthy (CTR) adult rats received ed-NGF twice a day for 2 weeks. Depressive phenotype was identified by force swimming test (FST). Proteins extracted from PFC were processed for ELISA and Western blot analyses to measure the expression of BDNF, proBDNF, and their receptors and intracellular signals. Results ed-NGF treatment modulates BDNF pathway in PFC and normalizes the STZ-induced BDNF alterations by stimulating TRK-mediated survival mechanism. A decreased latency in FST was also found in STZ rats, while no change was observed comparing CTR + NGF and STZ + NGF with CTR. Conclusion The present data confirm the capacity of ed-NGF treatment to affect brain neurons and lead to brain damage recovery by activating protective and remodeling pathways triggered by BDNF. We suggest that the ed-NGF-induced changes in BDNF signaling might influence the manifestation of depressive phenotype in diabetic rats.