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We previously revealed that hydrogen sulfide (H 2 S) attenuates chronic stress-induced cognitive impairment, but the underlying mechanism needs to be further clarified. Growth differentiation factor 11 (GDF11) plays an important regulatory role in cognitive function and that hippocampal NLRP3/caspase-1-mediated pyroptosis contributes to the pathogenesis of cognitive impairment. Hence, this research aimed to explore whether promoting GDF11 levels and suppressing hippocampal NLRP3/caspase-1-mediated pyroptosis mediate H 2 S to alleviate chronic stress-induced cognitive impairment. Sprague–Dawley rats were subjected to unpredictable chronic mild stress lasting four weeks to establish an animal model of chronic stress-induced cognitive impairment. Behavioral performance was assessed by the Y-maze test and the novel object recognition test. The expression levels of proteins were analyzed by Western blot analysis. The levels of IL-1β and IL-18 in the hippocampus were measured by ELISA. NaHS upregulated the expression of GDF11 in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats. Silencing GDF11 blocked NaHS-improved cognitive impairment in CUMS-exposed rats, according to the Y-maze test and the novel object recognition test. Furthermore, NaHS mitigated NLRP3/caspase-1-mediated pyroptosis in the hippocampus of CUMS-exposed rats and this effect was reversed by silencing GDF11. Moreover, overexpression of GDF11 alleviated CUMS-induced cognitive impairment and NLRP3/caspase-1-mediated hippocampal pyroptosis. GDF11 mediates H 2 S to attenuate chronic stress-induced cognitive impairment via inhibiting hippocampal NLRP3/caspase-1-mediated pyroptosis. [Display omitted] • H 2 S upregulates GDF11 expression and ameliorates pyroptosis in CUMS-exposed rats. • Silencing GDF11 blocks H 2 S to prevent cognitive dysfunction in CUMS-exposed rats. • Silencing GDF11 reverses H 2 S-blocking pyroptosis in CUMS-exposed rats. • GDF11 overexpression ameliorates the cognitive impairment in CUMS-exposed rats. • GDF11 overexpression inhibits pyroptosis in CUMS-exposed rats. [ABSTRACT FROM AUTHOR]

Depression is a highly prevalent comorbidity arising in patients with Parkinson's disease (PD). However, depression in patients with PD is poorly treated. Hydrogen sulfide (H 2 S), a neuromodulator, has the potential to relieve depression. To investigate whether H 2 S attenuates depression-like behaviours in a rat model of PD and examine the underlying mechanisms. We utilised rotenone to develop a PD model with subcutaneous injections in the dorsal cervical region of Sprague-Dawley rats. The depression-like behaviours in the rotenone-induced PD model rats were assessed through forced swimming, tail suspension, open field, novelty-suppressed feeding, and elevated plus-maze tests. The expression of postsynaptic density protein-95 and synapsin-1, related to synaptic plasticity, was detected using Western blot in the hippocampus. The hippocampal ultrastructure, including the synaptic density, length of the synaptic active zone, postsynaptic density thickness, and synaptic gap width, was detected using transmission electron microscopy. We proved that sodium hydrosulfide (NaHS; a donor of H 2 S) significantly attenuated the depression-like behaviours and disorders of hippocampal synaptic plasticity in rotenone-induced PD rats. Furthermore, inhibition of the hippocampal Warburg effect by 2-deoxyglucose abolished NaHS-enhanced hippocampal synaptic plasticity and reversed NaHS-attenuated depression-like behaviours in the rotenone-induced PD rats. H 2 S attenuates PD-associated depression by improving the hippocampal synaptic plasticity in a hippocampal Warburg effect-dependent manner. • H 2 S attenuates the depression-like behaviors in PD rats. • H 2 S prevents the disorders of hippocampal synaptic plasticity in PD rats. • Inhibited Warburg effect abolishes H 2 S-enhanced hippocampal synaptic plasticity. • Inhibited Warburg effect reverses H 2 S-attenuated depression-like behaviors. [ABSTRACT FROM AUTHOR]

Increasing evidence confirms that sleep deprivation (SD), which induces hippocampal neuroinflammation, is a risk factor for depression. Hydrogen sulfide (H 2 S) is a novel neuromodulator that plays antidepressant-like role. Silent mating type information regulation 2 homolog 1 (Sirt1) is well-characterized as a regulator of mood disorder. Furthermore, we have previously reported that H 2 S upregulates Sirt1 expression in the hippocampus of SD-exposed rats. Here, we explored whether H 2 S ameliorates depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory in SD-exposed rats and whether Sirt1 mediates these protective roles of H 2 S. In the present work, we showed that NaHS (a donor of H 2 S) significantly alleviated depression- and anxiety-like behaviors in the SD-exposed rats tested by novelty-suppressed feeding test (NST), forced swim test (FST), tail suspension test (TST), and elevated plus maze test (EPMT) and that NaHS attenuates neuroinflammatory in the hippocampus of SD-exposed rats, as evidenced by reducing the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokine CCL2, as well as increasing the levels of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. However, Sirt1 inhibitor reversed the protective effects of H 2 S against SD-induced depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory. In conclusion, H 2 S antagonizes SD-induced depression- and anxiety-like behaviors and neuroinflammation, which is required hippocampal Sirt1. These findings suggested that H 2 S is a novel approach to prevent SD-induced depression and anxiety. • H 2 S ameliorated SD-induced depression- and anxiety-like behaviors in rats. • H 2 S attenuated SD-induced neuroinflammatory responses in the hippocampus of rats. • Sirtinol abolished H 2 S to prevent depression- and anxiety-like behaviors. • Sirtinol blocked H 2 S to inhibit the hippocampal neuroinflammatory. [ABSTRACT FROM AUTHOR]

[Display omitted] β 2 -microglobulin (B 2 M) has been established to impair cognitive function. However, no treatment is currently available for B 2 M-induced cognitive dysfunction. Itaconate is a tricarboxylic acid (TCA) cycle intermediate that exerts neuroprotective effects in several neurological diseases. The amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD)/picolinic acid (PIC) pathway is a crucial neuroprotective branch in the kynurenine pathway (KP). The present study sought to investigate whether Itaconate attenuates B 2 M-induced cognitive impairment and examine the mediatory role of the hippocampal ACMSD/PIC pathway. We demonstrated that 4-Octyl Itaconate (OI, an itaconate derivative) significantly alleviated B 2 M-induced cognitive dysfunction and hippocampal neurogenesis impairment. OI treatment also increased the expression of ACMSD, elevated the concentration of PIC, and decreased the level of 3-HAA in the hippocampus of B 2 M-exposed rats. Furthermore, inhibition of ACMSD by TES-991 significantly abolished the protections of Itaconate against B 2 M-induced cognitive impairment and neurogenesis deficits. Exogenous PIC supplementation in hippocampus also improved cognitive performance and hippocampal neurogenesis in B 2 M-exposed rats. These findings demonstrated that Itaconate alleviates B 2 M-induced cognitive impairment by upregulation of the hippocampal ACMSD/PIC pathway. This is the first study to document Itaconate as a promising therapeutic agent to ameliorate cognitive impairment. Moreover, the mechanistic insights into the ACMSD/PIC pathway improve our understanding of it as a potential therapeutic target for neurological diseases beyond B 2 M-associated neurocognitive disorders. [ABSTRACT FROM AUTHOR]

Our previous works demonstrated that β2-microglobulin (β2m), a systemic pro-aging factor, induce depressive-like behaviors. Hydrogen sulfide (H 2 S) is identified as a potential target for treatment of depression. The aim of the present work is to explore whether H 2 S antagonizes β2m-induced depressive-like behaviors and the underlying mechanisms. The depressive-like behaviors were detected using the novelty suppressed feeding test (NSFT), tail suspension test (TST), forced swimming test (FST) and open field test (OFT). The expressions of Warburg-related proteins, including hexokinase II (HK II), pyruvate kinase M2 (PKM2), Lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase 1(PDK1), and synaptic plasticity-related proteins, including postsynaptic density protein 95 (PSD95) and synaptophysin1 (SYN1), were determined by western blotting. we found that NaHS (the donor of H 2 S) attenuated the depressive-like behaviors in the β2m-exposed rats, as judged by NSFT, TST, FST, and OFT. We also demonstrated that NaHS enhanced the synaptic plasticity, as evidenced by the upregulations of PSD95 and SYN1 expressions in the hippocampus of β2m-exposed rats. Furthermore, NaHS improved the Warburg effect in the hippocampus of β2m-exposed rats, as evidenced by the upregulations of HK II, PKM2, LDHA and PDK1 expressions, and the downregulation of PDH expression. H 2 S prevents β2m-induced depressive-like behaviors, which is involved in improvement of hippocampal synaptic plasticity as a result of enhancement of hippocampal Warburg effect. • H 2 S attenuates β2m-induced depressive-like behaviour. • H 2 S improves synaptic plasticity in the hippocampus of β2m-exposed rat. • H 2 S enhances Warburg effect in the hippocampus of β2m-exposed rat. • H 2 S prevents β2m-induced depression via Warburg effect- synaptic plasticity axis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Exposure of rats to homocysteine (Hcy) leads to learning and memory dysfunctions. [•] Hcy decreases the generation of endogenous H2S in the hippocampus of rats. [•] Hcy up-regulates the endoplasmic reticulum (ER) stress in the hippocampus of rats. [•] Disturbed H2S formation and ER stress involve in Hcy-caused memory disorder. [ABSTRACT FROM AUTHOR]

The mechanisms underlying formaldehyde (FA)-induced neurotoxicity have not yet been fully clarified. Ferroptosis is a novel regulatory cell death and the Warburg effect is involved in regulating neural function. In this study, we investigated whether FA-induced neurotoxicity is implicated in neuronal ferroptosis and determined whether the Warburg effect mediates FA-induced neuronal ferroptosis. We found that FA (0.1, 0.5 and 1.0 mM, 6 h) induced cell death in HT22 cells (a cell line of mouse hippocampal neuron), as evidenced by a decrease in cell viability and an increase in cell mortality; enhanced oxidative stress, as evidenced by a decrease in glutathione (GSH) and increases in malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), as well as reactive oxygen species (ROS); increased the iron content; and upregulated the ferroptosis-associated genes, including Ptgs2 (prostaglandin-endoperoxide synthase 2), GLS2 (glutaminase 2), solute carrier family 1 member 5 (SLC1A5), and solute carrier family 38 member 1 (SLC38A1) in HT22 cells, indicating the inductive role of FA in the ferroptosis of HT22 cells. Meanwhile, we found that FA (0.1, 1, 10 μmol) decreased the cross-sectional of mitochondria, increased the level of lipid ROS and iron content in primary hippocampal cells. We showed that FA (0.1, 0.5 and 1.0 mM, 6 h) upregulated the Warburg effect in HT22 cells, as evidenced by up-regulations of pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1(PDK-1), and lactate dehydrogenase (LDHA) proteins; down-regulation of pyruvate dehydrogenase (PDH); and an increase in lactate production. Also, we found that FA (0.1, 1, 10 μmol, 7 d) upregulated the Warburg effect in hippocampal tissue, as evidenced by up-regulations of PKM2, PDK-1, and LDHA proteins; down-regulation of PDH. Furthermore, the inhibition of the Warburg effect by dichloroacetate (DCA) protected HT22 cells against FA-induced ferroptosis and cell death. Collectively, these data indicated that FA induces ferroptosis in hippocampal neuronal cells by upregulation of the Warburg effect. [ABSTRACT FROM AUTHOR]