Exogenous Hydrogen Sulfide Ameliorates Diabetes-Associated Cognitive Decline by Regulating the Mitochondria-Mediated Apoptotic Pathway and IL-23/IL-17 Expression in db/db Mice

Abstract

Background: Diabetes-associated cognitive decline (DACD) is one of the complications of diabetes and leads to cognitive impairment and an increased risk of dementia. However, the exact mechanism of DACD has not been fully characterized, and a successful therapy for this issue has not been established. This study aimed to detect the anti-apoptotic and anti-inflammatory effects of hydrogen sulfide (H₂S) on DACD. Methods: We used a behavioural scoring method, Western blot, TUNEL staining and immunofluorescence staining to investigate the expression of the mitochondrial apoptotic pathway and the IL-23/IL-17 axis in db/db mice with or without sodium hydrosulfide (NaHS) administration. Results: NaHS administration mice exhibited reduced time to find the platform and a shorter swimming distance (P<0.05), while the time spent in the target quadrant was increased compared to that of the db/db group (P<0.05). Pro-apoptotic proteins, including cleaved Caspase-3, cleaved Caspase-9, Bax and cytochrome C, were elevated in the db/db group (P<0.01) but were downregulated in the db/db+NaHS group (P<0.05). Exogenous H₂S decreased the numbers of TUNEL-positive cells in the db/db mice (P<0.05). The Western blot analysis showed that the expression levels of IL-23/IL-17 were lower in the NaHS administration group than in the db/db group (P<0.05). Conclusion: We demonstrated that H₂S improved the spatial learning and memory abilities of the db/db mice by modulating the mitochondrial apoptotic pathway and the IL-23/IL-17 axis, which were found to be associated with DACD. H₂S treatment may help prevent the progression of apoptotic hippocampal neurons in db/db mice and inform the development of a new therapeutic target.

Upregulation of Tolerogenic Pathways by the Hydrogen Sulfide Donor GYY4137 and Impaired Expression of H2S-Producing Enzymes in Multiple Sclerosis

“…This suggests that the effects of H 2 S on T cells are direct, rather than indirect through other immune cells present in the isolates, such as macrophages/microglia. The inhibitory effects of H 2 S on IL-17 generation in the CNS have been previously reported [63], thus corroborating our findings.…”

Hydrogen Sulfide Decreases Blood-Brain Barrier Damage via Regulating Protein Kinase C and Tight Junction After Cardiac Arrest in Rats

“…Various studies have confirmed that H 2 S attenuates ischemic brain injury by mitigating oxidative stress, inhibiting cell apoptosis, opening K-ATP channels, relaxing blood vessels, and alleviating astrocytic activation [13,14,29]. Consistent with these previous findings, we found that H 2 S improved neurological function and increased survival rate after CA and resuscitation in the present study.…”

“…determined that endogenous H 2 S may be a special kind of neuromodulator. In the central nervous system (CNS), endogenous H 2 S is mainly generated through catalytic effects of 3-mercaptopyruvate sulfurtransferase and cystathionine-β-synthase on sulfur amino acids [13]. It is known that H 2 S is not only involved in the neuroendocrine adjustment by the hypothalamus-pituitary-adrenal axis [27], but also affects cerebral blood flow by relaxing microvascular smooth muscles [28].…”

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

“…IL-17 was also upregulated in all three diabetic models and was highly correlated with peripheral Aβ1-42 and with glucose levels in db/db mice. IL-17 is the most effective cytokine of T helper 17 cells and plays a proinflammatory role in chronic inflammation [73] observed in T2D [74]. Also, IL-17 production has been associated with cerebral small vessel disease, similar to that observed in db/db and APP/PS1xdb/db mice [75], and IL-17 might contribute to atherosclerosis development.…”

“…Moreover, IL-17 has been implicated in the neuroinflammatory response in AD [76], and while some controversial studies show a protective role for IL-17 against the risk for T2D [77], others support a crucial role for IL-17 in inflammation, insulin resistance, and T2D [66,78]. In line with these studies, IL-17 levels are also increased in the hippocampus from db/db mice [73], and antibodies targeting Th17 cells have been studied in an effort, to protect individuals at risk for developing diabetes [79]. These data support that metabolic alterations can broadly trigger and exacerbate brain neuroinflammation and production of cytokines known to promote T2D and AD pathogenesis [36,79].…”