Abstract
Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.
Highlights
Post-stroke depression (PSD) refers to a common neuropsychiatric complication characterized by low mood, loss of interest, and cognitive dysfunction, in addition to symptoms of neurological impairment after stroke [1,2,3]
ProBDNF levels in the PSD-like plus recombinant p75 neurotrophin receptor (p75NTR) and PSD-like plus siJNK groups were significantly lower than those in the PSD-like group (antFront: F(3,8) = 28.12, p < 0.001; p(A1 vs. D1) < 0.001, p(A1 vs. E1) < 0.01, p(A1 vs. F1) = 0.03, p(D1 vs. E1) < 0.01; p(D1 vs. F1) < 0.01, Fig. 1C), (Hippo: F(3,8) = 62.2, p < 0.0001; p(A2 vs. D2) < 0.001, p(A2 vs. E2) < 0.01, p(A2 vs. F2) = 0.01, p(D2 vs. E2) = 0.001; p(D2 vs. F2) < 0.01, Fig. 1D). These data indicate that p75NTR and Jun N-terminal kinase (JNK) are involved in the process of increasing proBDNF induced in the PSD-like model
There were two major findings: (i) proBDNF is involved in the pathophysiological process of PSD and (ii) proBDNF binds to the p75NTR receptor and activates Ras homolog gene family member A (RhoA)/JNK signaling to promote cellular apoptosis and inhibit the regeneration of nerve synapses, thereby promoting the pathogenesis of PSD
Summary
Post-stroke depression (PSD) refers to a common neuropsychiatric complication characterized by low mood, loss of interest, and cognitive dysfunction, in addition to symptoms of neurological impairment after stroke [1,2,3]. PSD hinders the recovery of neurological function and the ability of daily living in stroke patients, and is closely related to the social avoidance and high mortality of stroke patients [4, 5]. Stroke is the most direct cause of PSD; the specific mechanisms of PSD are unknown [6]. Several theories have been proposed, including the psychological stress theory, neurotransmitter theory, and inflammatory factor theory, these theories mainly focused on the patients’ clinical manifestations and related factors. Mature animal or cell models of PSD and basic research regarding PSD pathogenesis are lacking
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