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Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer’s disease, Parkinson’s disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.

Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. Methods We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells. Results Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. Conclusions These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.

Background In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. Methods Twenty-four female rats were divided into four groups randomly ( n  = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80–100% of V Max , 4–10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aβ) and Tau were also assessed using Western blot. Results An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. Conclusions HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

Diabetes‐related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes‐related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes‐related depression might be associated with the mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐glutamate receptor2 (GluR2)‐Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive‐like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu‐GluR2‐Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy‐induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐GluR2‐Parkin pathway, is responsible for depressive‐like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD.

Background/Objectives: Diabetes mellitus is often accompanied by mental health complications, including anxiety, depression, and cognitive decline. Recent research suggested that capsaicin, the active component of chili peppers, may influence mental health. This study aimed to determine the effect of dietary capsaicin on mental disorders in a type 1 diabetes (T1D) mouse model, while also exploring the potential involvement of the microbiota-gut-brain axis. Methods: We induced T1D in mice using streptozotocin (STZ) and administered a diet supplemented with 0.005% capsaicin for five weeks. Behavioral assessments, including the open field test (OFT), tail suspension test (TST), forced swimming test (FST), elevated plus maze (EPM) test, and Morris water maze (MWM) test, were conducted to evaluate depressive and anxiety-like behaviors as well as cognitive function. Targeted and untargeted metabolomics analyses were performed to assess neurotransmitter levels in the hippocampus and serum metabolites, while 16S rRNA sequencing was utilized to analyze gut microbiota composition. Intestinal barriers were determined using western blot detection of the tight junction proteins ZO-1 and occludin. Results: Dietary capsaicin exacerbated anxiety and depressive-like behaviors along with cognitive declines in T1D mice. Capsaicin reduced gut microbiota diversity and levels of beneficial bacteria, while broad-spectrum antibiotic treatment further intensified anxiety and depression behaviors. Metabolomic analysis indicated that capsaicin disrupted metabolic pathways related to tryptophan and phenylalanine, leading to decreased neuroprotective metabolites, such as kynurenic acid, hippurate, and butyric acid. Additionally, capsaicin diminished the expression of ZO-1 and occludin, indicating increased intestinal permeability. Conclusions: Dietary capsaicin aggravates gut microbiota and metabolic disturbances in diabetic mice, thereby worsening anxiety, depression, and cognitive decline.

Bacopa monnieri extract has been implicated in the recovery of memory impairments due to various neurological disorders in animal models and humans. However, the precise molecular mechanism of the role of CDRI-08, a well characterized fraction of Bacopa monnieri extract, in recovery of the diabetes mellitus-induced memory impairments is not known. Here, we demonstrate that DM2 mice treated orally with lower dose of CDRI-08 (50- or 100 mg/kg BW) is able to significantly enhance spatial memory in STZ-DM2 mice and this is correlated with a significant decline in oxidative stress and up regulation of the AMPA receptor GluR2 subunit gene expression in the hippocampus. Treatment of DM2 mice with its higher dose (150 mg/kg BW or above) shows anti-diabetic effect in addition to its ability to recover the spatial memory impairment by reversing the DM2-induced elevated oxidative stress and decreased GluR2 subunit expression near to their values in normal and CDRI-08 treated control mice. Our results provide evidences towards molecular basis of the memory enhancing and anti diabetic role of the Bacopa monnieri extract in STZ-induced DM2 mice, which may have therapeutic implications.

In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses. After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index. A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT. CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.

Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms. The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system. Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons. We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity. The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for understanding the interplay between T2D and cognitive decline and for designing effective preventive therapies.

Diabetic depression may be closely related to hippocampal inflammation. We hypothesized that Amomum tsao-ko Crevost et Lemaire ( A. tsao-ko ) might ameliorate depression-like behavior and glucose intolerance by modulating hippocampal inflammation. UPLC-Q-Exactive-MS/MS was used to identified the constituents in the ethanol extract of A. tsao-ko (EEAT). Then a diabetic depression (DD) model was established and treated for 4 weeks. Depression-like behaviors were assessed using the open field test, sucrose preference test and tail suspension test. The neuronal injury was observed by hematoxylin-eosin staining and Nissl staining. Oral glucose tolerance test, fasting blood glucose, hemoglobin Alc, fasting insulin and homeostasis model assessment of insulin resistance were used to evaluate the effects of EEAT on glucose metabolism. Serum lipids, neurotransmitters, neuroendocrine and inflammation levels were detected by biochemical kits and enzyme-linked immunosorbent assay. Activation of microglia markers was detected by immunofluorescence. Western blotting was used to detect the effect of EEAT on the HMGB1/TLR4/NF-κB protein expression. 48 chemical components were identified from EEAT. Animal experiments showed that EEAT improved the levels of glucose and lipid metabolism, alleviated depression-like behaviors, decreased the level of neurotransmitters and increased the secretion of neuroendocrine-related hormones. The activation of microglia and immunofluorescence intensity of neurogenesis also improved. At the same time, the expression of HMGB1, TLR4 and NF-κB proteins in the inflammatory pathway was also inhibited. EEAT had effects on improving DD symptoms, which may be achieved by down-regulating the HMGB1/TLR4/NF-κB protein expression. Graphical abstract

Diabetes is associated with behavioural and neurochemical alterations. In this manuscript, we are reporting the beneficial effects of parthenolide, an NF-κB inhibitor on behavioural and neurochemical deficits in type 2 diabetic rat model. Diabetes was induced by high-fat diet followed by low dose of streptozotocin (35 mg/kg). Elevated plus maze, open-field, MWM and passive avoidance test paradigm were used to assess behavioural and cognitive deficits. Three-week treatment of parthenolide (0.25 and 0.50 mg/kg; i.p. ) attenuated diabetes-induced alteration in cognitive function in Morris water maze and passive avoidance test. Anxiety-like behaviour was also reduced by parthenolide treatment. Moreover, TNF-α and IL-6 levels were significantly decreased in cortex and hippocampus of parthenolide-treated rats. Three-week parthenolide treatment also toned down the alteration of GABA and glutamate homoeostasis. Results of this study corroborate the involvement of neuroinflammation in the development of behavioural and neurochemical deficits in diabetic animals and point towards the therapeutic potential of parthenolide in diabetes-induced alteration of learning, memory and anxiety behaviour.