Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianopolis, SC, Brazil.
Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil.
Chem Biol Interact. 2021 Jun 1;342:109476. doi: 10.1016/j.cbi.2021.109476. Epub 2021 Apr 17.
Ketamine is the prototype for glutamate-based fast-acting antidepressants. The establishment of ketamine-like drugs is still a challenge and ascorbic acid has emerged as a candidate. This study investigated the ascorbic acid's ability to induce a fast antidepressant-like response and to improve hippocampal synaptic markers in mice subjected to chronic corticosterone (CORT) administration. CORT was administered for 21 days, followed by a single administration of ascorbic acid (1 mg ∕Kg, p.o.), ketamine (1 mg ∕Kg, i.p.) or fluoxetine (10 mg ∕Kg, p.o.) in mice. Depressive-like behavior, hippocampal synaptic proteins immunocontent, dendrite spines density in the dentate gyrus (DG) were analyzed 24 h following treatments. The administration of ascorbic acid or ketamine, but not fluoxetine, counteracted CORT-induced depressive-like behavior in the tail suspension test (TST). CORT administration reduced PSD-95, GluA1, and synapsin (synaptic markers) immunocontent, and these alterations were reversed by ascorbic acid or ketamine, but only ketamine reversed the CORT-induced reduction on GluA1 immunocontent. In the ventral and dorsal DG, CORT decreased filopodia-, thin- and stubby-shaped spines, while ascorbic acid and ketamine abolished this alteration only in filopodia spines. Ascorbic acid and ketamine increased mushroom-shaped spines density in ventral and dorsal DG. Therefore, the results show that a single administration of ascorbic acid, in a way similar to ketamine, rapidly elicits an antidepressant-like response and reverses hippocampal synaptic deficits caused by CORT, an effect associated with increased levels of synaptic proteins and dendritic remodeling.
氯胺酮是基于谷氨酸的快速抗抑郁药的原型。氯胺酮样药物的建立仍然是一个挑战，抗坏血酸已成为一种候选药物。本研究探讨了抗坏血酸诱导快速抗抑郁样反应的能力，并改善了慢性皮质酮（CORT）给药后小鼠的海马突触标志物。CORT 给药 21 天，随后单次给予抗坏血酸（1mg ∕Kg，p.o.）、氯胺酮（1mg ∕Kg，i.p.）或氟西汀（10mg ∕Kg，p.o.）。在处理后 24 小时分析抑郁样行为、海马突触蛋白免疫含量、齿状回（DG）中的树突棘密度。抗坏血酸或氯胺酮给药，但不是氟西汀，可拮抗 CORT 诱导的悬尾试验（TST）中的抑郁样行为。CORT 给药降低了 PSD-95、GluA1 和突触素（突触标志物）的免疫含量，抗坏血酸或氯胺酮逆转了这些变化，但只有氯胺酮逆转了 CORT 诱导的 GluA1 免疫含量减少。在腹侧和背侧 DG 中，CORT 减少了丝状、薄和短棘突，而抗坏血酸和氯胺酮仅在丝状棘突中消除了这种变化。抗坏血酸和氯胺酮增加了腹侧和背侧 DG 中蘑菇形棘突的密度。因此，这些结果表明，单次给予抗坏血酸，以类似于氯胺酮的方式，迅速引发抗抑郁样反应，并逆转 CORT 引起的海马突触缺陷，这种作用与突触蛋白水平升高和树突重塑有关。
