k252a Inhibits H 2 S-Alleviated Homocysteine-Induced Cognitive Dysfunction in Rats

Homocysteine (Hcy) is a neurotoxicity amino acid that causes cognitive dysfunction. Hydrogen sulfide (H 2 S) is a neuroprotective gas molecular and can improve cognitive ability in a range of physiological concentrations. Our previous study confirmed that H 2 S (by its donor, NaHS) ameliorates cognitive impairment in Hcy-exposed rats, but the underlying mechanism has not been well elucidated. Accumulating evidence suggests that k252a, the furanosylated indolocarbazoleas, is usually used as the receptor tyrosine kinase B (TrkB) antagonist and blocks brain-derived neurotrophic factor (BDNF)/TrkB signaling, thus leading to cognitive decline. Interestingly, we previously demonstrated that k252a reversed H 2 S alleviated Hcy-induced endoplasmic reticulum stress and neuronal apoptosis via inhibiting BDNF-TrkB pathway. Therefore, we assumed that k252a might inhibit the protective effect of H 2 S on Hcy-induced cognitive dysfunction. We used Hcy to establish a rat model of cognitive impairment. We found that after administration of k252a by intracerebroventricular injection, the beneficial effect of H 2 S on Hcy-induced cognitive decline is abolished, as reflected by the increasing escape latency and time spent in the target quadrant in the Morris Water Maze (MWM) test as well as decreased spontaneous alternation in Y-maze test and the lower discrimination index in the Novel Object Recognition (NOR) test in rats co-treated with sodium hydrosulfide (NaHS, a donor of H 2 S), Hcy and k252a. Our findings suggested that k252a antagonized the effect of H 2 S on preventing Hcy-related cognitive decline. Our finding expands the understanding of the potential mechanism on the resistant role of H 2 S in Hcy-caused cognitive damage.