7, 8-dihydroxyflavone Ameliorates Cholinergic Dysfunction, Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Vascular Dementia.

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD. VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20 mg/kg) and Donepezil (10 mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1ß, and NF-kß), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats. Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus. These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.

Tetramethylpyrazine Attenuates Cognitive Impairment Via Suppressing Oxidative Stress, Neuroinflammation, and Apoptosis in Type 2 Diabetic Rats.

Cognitive dysfunction is an important complication observed in type 2 diabetes mellitus (T2DM) patients. Tetramethylpyrazine (TMP) is known to exhibit anti-diabetic and neuroprotective properties. Therefore, the present study aimed to investigate the possible therapeutic effects of TMP against type 2 diabetes-associated cognitive impairment in rats. High-fat diet (HFD) followed by a low dose of streptozotocin (35 mg/kg) was used to induce diabetes in Sprague-Dawley rats. TMP (20, 40, and 80 mg/kg) and Pioglitazone (10 mg/kg) were administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NOR) tests were used to assess memory function. Fasting blood glucose (FBG), lipid profile, HOMA-IR, glycosylated hemoglobin (HbA1c), and glucose tolerance were measured. Acetylcholinesterase (AChE) and choline acetytransferase (ChAT) activity, acetylcholine (ACh) levels, oxidative stress, apoptotic (Bcl-2, Bax, caspase-3), and inflammatory markers (TNF-α, IL-1ß, and NF-kß) were assessed. BDNF, p-AKT, and p-CREB levels were also measured. In the present work, we observed that treatment of diabetic rats with TMP alleviated learning and memory deficits, improved insulin sensitivity, and attenuated hyperglycemia and dyslipidemia. Furthermore, treatment with TMP increased BDNF, p-Akt, and p-CREB levels, normalized cholinergic dysfunction, and suppressed oxidative, inflammatory, and apoptotic markers in the hippocampus. Collectively, our results suggest that the TMP may be an effective neuroprotective agent in alleviating type 2 diabetes-associated cognitive deficits.

α7nAChR activation protects against oxidative stress, neuroinflammation and central insulin resistance in ICV-STZ induced sporadic Alzheimer's disease.

Central insulin resistance is considered as one of the pathological hallmarks of Alzheimer's disease (AD), similar to formation of amyloid plaques and neurofibrillary tangles (NFT). Activation of α7nAChR by GTS-21 has been indicated to reverse peripheral insulin resistance and exert neuroprotection. Therefore, the aim of the present study was to determine the effect of α7nAChR agonist (GTS-21) on intracerebroventricular administration of streptozotocin (ICV-STZ)-induced oxidative stress, neuroinflammation, cholinergic dysfunction, central insulin resistance and cognitive deficits. GTS-21 (1, 4 and 8 mg/kg; i.p.) was administered for 21 days following bilateral ICV-STZ administration (3 mg/kg) in C57BL/6 mice. Neurobehavioral assessments were performed using Morris water maze (MWM) and novel object recognition (NOR). Inflammatory markers (TNF-α, IL-6 and IL-1ß) were determined using ELISA. Oxido-nitrosative stress (GSH, MDA and nitrite) and cholinergic activity (acetylcholine esterase and choline acetyltransferase) were estimated in the cortex and hippocampus through biochemical methods. Gene expression of insulin receptor (IR), IRS1, IRS2, BACE1, APP, PI3-K, AKT and GSK3ß were determined by q-RT-PCR. ICV-STZ administration induced memory impairment, increased oxidative stress and neuroinflammation, and caused cholinergic dysfunction. Our results demonstrated that activation of α7nAChR by GTS-21 treatment improved memory in MWM and NOR test. Moreover, GTS-21 treatment significantly decreased oxido-nitrosative stress, inflammatory markers and cholinergic dysfunction in cortex and hippocampus. Finally, GTS-21 treatment restored ICV-STZ induced downregulation of IR, IRS1, IRS2, PI3-k, Akt and attenuated GSK3ß, APP and BACE-1 indicating improved insulin signalling. Therefore, activation of α7nAChR through GTS-21 might be the potential target for the amelioration of central insulin resistance induced AD.

7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer's disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance.

RATIONALE: Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer's disease (SAD) characterized by tau pathology and neurodegeneration arising from oxidative stress, mitochondrial dysfunction, and insulin resistance. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid having antioxidant property interlinked with mitochondrial functioning and insulin actions. OBJECTIVES: To evaluate the neuroprotective and cognitive enhancement properties of 7,8-DHF in an ICV-STZ rat model of SAD. METHODS: ICV-STZ (3 mg/kg) was injected into male Wistar rats. Cognitive functions were evaluated by Morris water maze (MWM) and novel object recognition (NOR). 7,8-DHF (5 mg/kg, 10 mg/kg, and 20 mg/kg) and rivastigmine (2 mg/kg) were given orally for 21 days. Reduced glutathione (GSH), catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), lipid peroxidation (LPO), protein carbonylation (PCO), and nitrite assays were performed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were determined. ELISA for the insulin-degrading enzyme (IDE) and p-tau was done. Histopathology was investigated by hematoxylin and eosin staining. RESULTS: 7,8-DHF treatment attenuated ICV-STZ-induced cognitive deficit in MWM and NOR. Moreover, in the cortex and hippocampus regions of the brain, GSH, catalase, SOD, GPX, LPO, PCO, and nitrite levels were reversed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were also normalized. IDE and p-tau protein were found to be significantly altered. 7,8-DHF provided protection from neuronal cell death examined in histopathology. CONCLUSIONS: Conclusively, 7,8-DHF was found to be neuroprotective in the ICV-STZ rat model by ameliorating oxidative stress, mitochondrial dysfunction, and insulin resistance, thereby improving cognitive functions evident with the behavioral results.

Activation of the Nrf2/HO-1 signaling pathway by dimethyl fumarate ameliorates complete Freund's adjuvant-induced arthritis in rats.

The nuclear factor erythroid 2-related factor (Nrf2) signaling pathway has recently emerged as a novel therapeutic target in treating various diseases. Therefore, the present study aimed to assess the protective role of the Nrf2 activator, dimethyl fumarate (DMF) in the complete Freund's adjuvant (CFA)- induced arthritis model. DMF (25, 50, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered for 14 days. Pain-related tests, paw volume, and arthritic scores were measured weekly. Serum TNF-α, IL-1ß, cyclic citrullinated peptide (CCP), C-reactive protein (CRP), and rheumatoid factor (RF) levels were estimated. Nitrite, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and myeloperoxidase (MPO) levels were also evaluated. NF-κB, Nrf2, HO-1, and COX-2 levels were estimated in the joint tissue. DMF treatment exerted anti-arthritic activity by enhancing the nociceptive threshold, improving arthritis scores, and reducing paw edema. Also, DMF suppressed changes in oxidative stress markers and inflammatory mediators and enhanced Nrf2 and HO-1 levels in CFA-injected rats. These findings indicate that the anti-arthritic activity of DMF may be mediated by the activation of the Nrf2/HO-1 pathway, which reduced oxidative damage and inflammation.

Dimethyl fumarate attenuates 2-VO-induced vascular dementia via activating the Nrf2 signaling pathway in rats.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia. METHODS: Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague-Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus. RESULTS: The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1ß, NF-κß, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment. CONCLUSION: Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia.

Beneficial effects of ferulic acid alone and in combination with insulin in streptozotocin induced diabetic neuropathy in Sprague Dawley rats.

BACKGROUND: Ferulic acid (FA) is a phenolic phytochemical known to protect against various diabetic complications. However, its role in diabetic neuropathy is still unclear. The present study investigated the potential protective effects of FA alone and its combination with insulin against streptozotocin (STZ)-induced diabetic neuropathy in rats. METHODS: STZ (55 mg/kg) was injected in adult Sprague-Dawley rats to induce diabetes. Diabetic rats were treated with FA (25, 50, and 100 mg/kg, p.o), insulin (10 IU/kg, s.c.) and the combination of FA (100 mg/kg, p.o.) with insulin (10 IU/kg, s.c.) for four weeks. Body weight, blood glucose, insulin, glycosylated hemoglobin, nerve conduction velocity and pain parameters were measured. Moreover, oxidative stress, inflammatory (TNF-α, IL-1ß, COX-2) and apoptotic markers (Bcl-2, Bax, caspase 3) were assessed in the sciatic nerve tissue. Na+-K+-ATPase activity and nerve growth factor (NGF) levels were also determined. RESULTS: FA attenuated STZ induced alteration in metabolic parameters, nociceptive threshold, motor nerve conduction velocity, NGF levels and Na+-K+-ATPase activity. In addition, FA boosted anti-oxidant defenses and suppressed oxidative stress, pro-inflammatory mediators and apoptotic markers. Furthermore, diabetic rats treated with insulin-FA (100 mg/kg) combination demonstrated more pronounced beneficial effects as compared to either agent alone. CONCLUSIONS: Collectively, our results suggest that FA either alone or in combination with insulin therapy could serve as an efficacious agent for treating diabetic neuropathy.

Astaxanthin attenuates oxidative stress and inflammatory responses in complete Freund-adjuvant-induced arthritis in rats.

BACKGROUND: Astaxanthin (ATX), a natural xanthophyll carotenoid, has shown to exert significant protective effects against various diseases via its antioxidant and anti-inflammatory properties. However, its potential role in arthritis is still not reported. Therefore, the aim of the present study was to investigate the potential anti-arthritic properties of ATX against complete Freund's adjuvant (CFA)-induced arthritis rats. METHODS: Adjuvant arthritis was induced by single intraplantar injection of complete Freund's adjuvant (CFA) in the left hind paw of adult female Wistar rats. ATX (25, 50 and 100 mg/kg) and indomethacin (5 mg/kg) were given orally from days 14 to 28. The anti-arthritic activity was evaluated through various nociceptive behavioral tests (mechanical allodynia, mechanical hyperalgesia, cold allodynia, and thermal hyperalgesia), paw edema assessment, and arthritis scores. Serum tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and cyclic citrullinated peptide (CCP) antibody levels were assessed. Moreover, malondialdehyde (MDA), nitrite, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were also evaluated. RESULTS: Oral administration of ATX (50 and 100 mg/kg) exhibited significant anti-arthritic activity via enhancing the nociceptive threshold, reducing paw edema and improving arthritis scores. Moreover, ATX treatment also markedly suppressed inflammatory and oxidative mediators in adjuvant-administered rats. CONCLUSIONS: Our findings suggest that ATX possesses potential anti-arthritic activity, which could be attributed to its anti-inflammatory and antioxidant properties.

Chromium picolinate attenuates cognitive deficit in ICV-STZ rat paradigm of sporadic Alzheimer's-like dementia via targeting neuroinflammatory and IRS-1/PI3K/AKT/GSK-3ß pathway.

Alzheimer's disease (AD) is prevalent in old age people and is one of the most common brain diseases. Brain insulin resistance, neuroinflammation, oxidative stress, and mitochondrial and cholinergic dysfunction are key features of the disease. In our study, streptozotocin (STZ) in a dose of 3 mg/kg was injected in male Wistar rats bilaterally through the intracerebroventricular (ICV) route on stereotaxic apparatus. Chromium picolinate (CrPic) was tested at doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, while rivastigmine (2 mg/kg) was used as reference standard drug. Cognitive dysfunction induced by STZ was assessed by behavioral tests like Morris water maze and novel object recognition test. Treatment with CrPic revealed attenuation of cognitive deficit. This was confirmed by behavioral tests, biochemical estimations of antioxidant enzymes, oxidative stress, nitrosative stress, and cholinergic and mitochondrial activity. CrPic did not change AchE activity significantly. STZ-induced neuroinflammation evident by increased TNF-α, IL-6, and CRP levels was also significantly decreased by CrPic. Dysfunctional insulin signaling after ICV-STZ was demonstrated by reduced IRS-1, PI3K, AKT, BDNF gene expression, and increased GSK-3ß, NF-κB gene expression with the help of qRT-PCR. CrPic treatment produced an improvement in insulin signaling revealed by increased gene expression of IRS-1, PI3-K, AKT, BDNF, and decreased gene expression of GSK-3ß and NF-κB. It was concluded that CrPic reversed AD pathology revealed by improved memory, reduced oxidative stress, neuroinflammation, mitochondrial dysfunction, and upregulated insulin signaling.

Pharmacological rewriting of fear memories: A beacon for post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychopathological response that develops after exposure to an extreme life-threatening traumatic event. Its prevalence ranges from 0.5% to 14.5% worldwide. Due to the complex pathophysiology of PTSD, currently available treatment approaches are associated with high chances of failure, thus further research to identify better pharmacotherapeutic approaches is needed. The traumatic event associated with fear memories plays an important role in the development of PTSD and could be considered as the main culprit. PTSD patient feels frightened in a safe environment as the memories of the traumatic event are revisited. Neurocircuit involving normal processing of fear memories get disturbed in PTSD hence making a fear memory to remain to dominate even after years of trauma. Persistence of fear memories could be explained by acquisition, re-(consolidation) and extinction triad as all of these processes have been widely explored in preclinical as well as clinical studies and set a therapeutic platform for fear memory associated disorders. This review focuses on neurocircuit and pathophysiology of PTSD in context to fear memories and pharmacological targeting of fear memory for the management of PTSD.

The Probiotic Mixture VSL#3 Reverses Olanzapine-Induced Metabolic Dysfunction in Mice.

Atypical antipsychotic drugs (AAPDs) such as olanzapine (OLZ) are associated with serious metabolic adverse effects such as weight gain, visceral fat accretion, glucose intolerance, and lipid abnormalities. Compelling evidence suggests that the gut microbiota is known to regulate metabolic homeostasis and therefore microbiota-modulating strategies such as probiotics may serve as an excellent approach for treating metabolic adverse effects associated with atypical antipsychotic drugs (AAPDs). The therapeutic potential of VSL#3 (20 × 109 CFU/day), in reversing olanzapine-induced metabolic dysfunction, was assessed. VSL#3 administration led to attenuation of OLZ-induced body weight gain, uterine fat deposition, impaired glucose tolerance, and insulin resistance. Moreover olanzapine treatment also decreased inflammatory markers, abolished oxidative stress in the vWAT, and prevented shifts in gut microbiota abundance levels. These results indicate that VSL#3 via its ability to manipulate the gut microbiome confers beneficial metabolic effects and may, therefore, represent a novel therapeutic approach for reversing antipsychotic-induced metabolic dysfunction.

Healthcare costs and nonadherence among chronic opioid users.

OBJECTIVES: To assess the health economic burden of chronic opioid users and to determine whether opioid regimen nonadherence contributes to increased healthcare costs. STUDY DESIGN: Retrospective claims-based analysis of patients with long-term prescription opioid use (>120 days of supply over 6 months). METHODS: Twelve-month healthcare utilization and costs were compared for chronic opioid users (n = 49,425) and, among chronic opioid users with urine drug-monitoring results (n = 2100), between adherent patients versus patients with evidence of nonadherence to their opioid regimen. Likely nonadherence was based on urine test results indicating absence of the prescribed drug, higher or lower than expected drug levels based on a proprietary algorithm, or presence of unprescribed or illegal drugs. The influence of nonadherence on total healthcare costs was assessed using multivariate models. RESULTS: Prevalence of chronic opioid use was 1.3%. Chronic opioid users had significantly greater healthcare utilization and costs than matched nonusers ($23,049 vs $4975; P <.001). Adherent patients (n = 442) had lower total healthcare costs than likely nonadherent patients (n = 1658; $23,160 vs $26,433; P = .036). After adjustment for demographics, likely nonadherence was significantly associated with elevated total healthcare costs (cost ratio [CR] 1.136; 95% confidence interval [CI] 1.00, 1.29; P = .048). When adjusting for other types of nonadherence, the presence of higher than expected levels of the prescribed opioid was associated with significantly elevated costs (CR 1.121; 95% CI 1.01, 1.25; P = .039). CONCLUSION: Chronic opioid users represent a substantial cost burden relative to similar patients without evidence of chronic pain. Among likely nonadherent chronic opioid users, those with evidence of opioid overuse had significantly elevated healthcare costs.