LncRNA XR_351665 Contributes to Chronic Pain-Induced Depression by Upregulating DNMT1 via Sponging miR-152-3p.

Chronic pain is frequently comorbid with depression. However, the mechanisms underlying chronic pain-induced depression remain unclear. Here, we found that DNA methyltransferase 1 (DNMT1) was upregulated in the central amygdala (CeA) of spared nerve injury (SNI)-induced chronic pain-depression rats, and knockdown of DNMT1 could improve the depression-like behaviors in SNI rats. Additionally, a panel of differentially expressed lncRNAs, including 38 upregulated and 12 downregulated lncRNAs, were identified by microarray analysis. Bioinformatics analysis suggested that the upregulated lncRNA XR_351665 was the upstream molecule to regulate DNMT1 expression. The knockdown of XR_351665 significantly alleviated the depression-like behaviors in SNI rats, whereas overexpression of XR_351665 induced the depression-like behaviors in naïve rats. Further mechanism-related researches uncovered that XR_351665 functioned as a competing endogenous RNA (ceRNA) to upregulate DNMT1 by competitively sponging miR-152-3p, and subsequently promoted the development of chronic pain-induced depression. Our findings suggest that lncRNA XR_351665 is involved in the development of chronic pain-induced depression by upregulating DNMT1 via sponging miR-152-3p. These data provide novel insight into understanding the pathogenesis of chronic pain-induced depression and identify a potential therapeutic target. PERSPECTIVE: LncRNA XR_351665 in CeA functions as a ceRNA to block the inhibitory effect of miR-152-3p on DNMT1 and contributes to the development of chronic pain-induced depression. These data suggest that manipulation of XR_351665/miR-152-3p/DNMT1 axis may be a potential method to attenuate chronic pain-induced depression.

SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress.

Numerous studies have shown that mitochondrial dysfunction manifested by increased mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) level, and decreased mitochondrial membrane potential (MMP) plays an important role in the development of neuropathic pain. Sirtuin3 (SIRT3), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, has been shown to inhibit mitochondrial oxidative stress. However, the role of SIRT3 in neuropathic pain is unclear. In this study, we found that the protein and mRNA levels of SIRT3 were significantly downregulated in the spinal cords of spared nerve injury- (SNI-) induced neuropathic pain mice, while overexpression of spinal SIRT3 reversed SNI-induced pain hypersensitivity. Further study showed that SIRT3 overexpression reduced the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), the regulatory component of the mPTP, inhibited the mPTP opening, decreased ROS and malondialdehyde (MDA) levels, and increased MMP and manganese superoxide dismutase (MnSOD) in SNI mice. Point mutation of K166 to arginine on CypD (CypD-K166R) abrogated SNI-induced mitochondrial dysfunction and neuropathic pain in mice. Moreover, inhibiting mPTP opening by cyclosporin A (CsA) improved mitochondrial function and neuropathic pain in SNI mice. Together, these data show that SIRT3 is necessary to prevent neuropathic pain by deacetylating CypD-K166 and further improving mitochondrial dysfunction. This study may shed light on a potential drug target for the treatment of neuropathic pain.

LncRNA-84277 is involved in chronic pain-related depressive behaviors through miR-128-3p/SIRT1 axis in central amygdala.

Long-term chronic pain can lead to depression. However, the mechanism underlying chronic pain-related depression remains unclear. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC). Our previous studies have demonstrated that SIRT1 in the central nucleus of the amygdala (CeA) is involved in the development of chronic pain-related depression. In addition, increasing studies have indicated that long non-coding RNAs (lncRNAs) play a vital role in the pathogenesis of pain or depression. However, whether lncRNAs are involved in SIRT1-mediated chronic pain-related depression remains largely unknown. In this study, we identified that a novel lncRNA-84277 in CeA was the upstream molecule to regulate SIRT1 expression. Functionally, lncRNA-84277 overexpression in CeA significantly alleviated the depression-like behaviors in spared nerve injury (SNI)-induced chronic pain rats, whereas lncRNA-84277 knockdown in CeA induced the depression-like behaviors in naïve rats. Mechanically, lncRNA-84277 acted as a competing endogenous RNA (ceRNA) to upregulate SIRT1 expression by competitively sponging miR-128-3p, and therefore improved chronic pain-related depression-like behaviors. Our findings reveal the critical role of lncRNA-84277 in CeA specifically in guarding against chronic pain-related depression via a ceRNA mechanism and provide a potential therapeutic target for chronic pain-related depression.

Hippocampal SIRT1 improves cognitive impairment by deacetylating tau protein in diabetic models.

Diabetes mellitus (DM) is associated with accelerated cognitive decline. However, the mechanism of diabetic cognitive impairment remains poorly understood. In this study, we found that the expression of Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, was downregulated significantly in the hippocampus of streptozotocin (STZ)-induced diabetic cognitive impairment rats. Viral overexpression of hippocampal SIRT1 ameliorated cognitive impairment in diabetic rats, but viral knockdown of hippocampal SIRT1 mimicked the diabetic effect, eliciting the cognitive decline in normal animals. Further study showed that the decreased level of SIRT1 may result in the increase of acetylated tau protein in the hippocampus, which may mediate the development of diabetic cognitive impairment. These results suggest that SIRT1 may be a key epigenetic regulator that guards against the development of diabetic cognitive impairment by deacetylating the tau protein. SIRT1 activator may serve as a new therapeutic approach for the treatment of diabetic cognitive impairment.

SIRT3 alleviates neuropathic pain by deacetylating FoxO3a in the spinal dorsal horn of diabetic model rats.

BACKGROUND: The underlying mechanisms of neuropathic pain remain unclear. This work aimed to investigate the role of Sirtuin3 (SIRT3), an nicotinamide adenosine dinucleotide+-dependent histone deacetylase, in the development of neuropathic pain induced by type 2 diabetes mellitus (T2DM) and to explore the associated mechanisms. METHODS: Diabetic neuropathic pain (DNP) in rats was induced by high-fat diet/low-dose streptozotocin. The pain behaviors were examined using the von Frey and Hargreaves tests. The levels of SIRT3, manganese superoxide dismutase (MnSOD) and catalase (CAT) were determined using Western blot and RT-qPCR. The acetylation, phosphorylation and ubiquitination of forkhead box class O3a (FoxO3a) were analyzed by immunoprecipitation and Western blot. RESULTS: SIRT3 expression and activity were significantly reduced in the spinal dorsal horn of DNP model rats. Overexpression of spinal SIRT3 reversed the pain hypersensitivity in the DNP model rats, but knockdown of spinal SIRT3 mimicked the pain effect, eliciting pain hypersensitivity in normal rats. Moreover, overexpression of spinal SIRT3 in DNP model rats increased the FoxO3a level and upregulated the antioxidant genes MnSOD and CAT by deacetylating FoxO3a and inhibiting FoxO3a phosphorylation and ubiquitination. Knockdown of spinal SIRT3 in normal rats decreased the FoxO3a level and downregulated MnSOD and CAT by inhibiting the deacetylation of FoxO3a and further increasing FoxO3a phosphorylation and ubiquitination. CONCLUSIONS: These results suggest that, by deacetylating FoxO3a and further reducing its phosphorylation, ubiquitination and degradation in the spinal dorsal horn, SIRT3 stabilizes FoxO3a protein and inhibits oxidative stress, resulting in pain alleviation in T2DM model rats.