Expression of pro- and mature brain neurotrophic factor and Bcl-xL in the hippocampus of neonatal rats under dexamethasone treatment

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Abstract

Due to the key role of neurotrophins in brain development and plasticity, the question of whether and how the precursor of brain-derived neurotrophic factor (proBDNF) can influence the active elimination of excess cells by apoptosis is of great importance. It is supposed that proneurotrophins selectively activate the neurotropin receptor p75, thereby inducing proapoptotic signaling pathways, while mature BDNF (matBDNF) has an antiapoptotic effect. Rationale: proBDNF and matBDNF will exhibit specific expression patterns that modify the process of apoptosis in the brain of neonatal rats under induction by glucocorticoids. Thus, the study examined the effect of the glucocorticoid dexamethasone (DEX) on the levels of mRNA of BDNF and the key protease of apoptosis caspase-3, the number of cells expressing active caspase-3, as well as the proteins proBDNF, matBDNF and the key anti-apoptotic protein BCL-xL in the hippocampus of 3–4 day old rat pups in 6 or 24 hours after DEX administration. In 6 hours, DEX induced anti-apoptotic processes, namely, it increased the levels of bdnf mRNA in the whole hippocampus, as well as the content of matBDNF and Bcl-xL proteins in the CA1-3 fields and the dentate gyrus. In this case, a temporary predominance of matBDNF expression over apoptogenic proBDNF was formed against the background of a constant number of cells expressing active caspase-3. In 24 hours, DEX provoked an increase in the expression of apoptogenic proBDNF, and its prevalence over mature neurotrophin in all fields of the hippocampus, accompanied by an increase in the number of cells, expressing active caspase-3. Moreover, we found a significant correlation between the proBDNF/matBDNF ratio and active caspase-3 in all three areas of the hippocampus. It has been shown that proBDNF has its own expression pattern—different from its mature form—in the hippocampus of neonatal rats upon DEX induction and the manifestation of its proapoptotic effect is accompanied by an increase in the proBDNF/matBDNF ratio.

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About the authors

V. V. Bulygina

The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: veta@bionet.nsc.ru
Russian Federation, Novosibirsk

T. S. Kalinina

The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences; Novosibirskiy State University

Email: veta@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

D. А. Lanshakov

The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences; Novosibirskiy State University

Email: veta@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

P. N. Menshanov

Novosibirskiy State University

Email: veta@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

E. V. Suhareva

The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences

Email: veta@bionet.nsc.ru
Russian Federation, Novosibirsk

N. N. Dygalo

The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences; Novosibirskiy State University

Email: veta@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

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2. Fig. 1. BDNF levels in the hippocampal regions of neonatal rats 6 hours (a) and 24 hours (b) after dexamethasone administration as a percentage of the saline group. ***p < 0.001 compared with saline, ###p < 0.001 compared with the corresponding 6-hour groups. Representative micrographs: matBDNF protein ‒ green signal (Alexa-488 fluorophore) (c ‒ 6 hours after saline administration, g ‒ 6 hours after dexamethasone administration).

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3. Fig. 2. ProBDNF levels in neonatal rat hippocampal regions 6 hours (a) and 24 hours (b) after dexamethasone administration as a percentage of the saline group. *p < 0.05; **p < 0.01 compared with saline, #p < 0.05; ###p < 0.001 compared with the corresponding 6-hour groups. Representative micrographs: proBDNF protein ‒ red signal (Alexa-594 fluorophore) (c ‒ 24 hours after saline administration, d ‒ 24 hours after dexamethasone administration).

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4. Fig. 3. Ratio of proBDNF to matBDNF levels in hippocampal regions of neonatal rats 6 hours (a) or 24 hours (b) after dexamethasone administration as a percentage relative to the saline group. *p < 0.05, **p < 0.01; &p=0.05 compared to saline, ###p < 0.001 compared to the corresponding 6-hour groups.

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5. Fig. 4. Bcl-xL levels in the hippocampal regions of neonatal rats 6 hours (a) and 24 hours (b) after dexamethasone administration. ***p < 0.001 compared with saline administration, ##p < 0.01, ###p < 0.001 compared with the corresponding 6-hour groups.

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6. Fig. 5. Number of cells expressing active caspase-3 in hippocampal regions of neonatal rats 6 hours (a) or 24 hours (b) after dexamethasone administration. **p < 0.01 compared with saline administration, ##p < 0.01 compared with the corresponding 6-hour groups. Representative micrographs: cells expressing active caspase-3 ‒ green signal (Alexa-488 fluorophore) (c ‒ 24 hours after saline administration, g ‒ 24 hours after dexamethasone administration).

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