Levothyroxine attenuates behavioral impairment and improves oxidative stress and histological alteration 3-nitropropionic acid induced experimental Huntington's disease in rats.

Huntington's disease (HD) is a neurodegenerative disorder characterized by degeneration of the striatum; it results in oxidative stress and motor deficits. Thyroid hormones regulate oxidative metabolism. In the present study, we evaluated the effect of administration of levothyroxine (LT-4) on neurobehavioral, oxidative stress, and histological changes in a rat model of HD. Forty-eight Wistar male rats were divided into the following six groups (n = 8): Group 1 (control) received physiological saline intraperitoneally (ip). Groups 2 and 3 received L-T4,30 and L-T4100 (µg/kg, ip, respectively) daily for 7 days. Group 4 (HD) received 3-nitropropionic acid (3-NP) (25 mg/kg, ip) daily for 7 days. Groups 5 and 6 received L-T4,30 and L-T4100 (µg/kg, ip, respectively) 30 min after 3-NP (25 mg/kg, ip) injection for the same duration. On the 8th day, behavioral parameters were evaluated with the Rotarod, Narrow beam walk, and Limb withdrawal tests. Oxidative markers such as Malondialdehyde (MDA) and Glutathione (GSH) levels and Superoxide dismutase (SOD) activity, in striatum tissue were measured. Moreover, striatum tissues were analyzed by Hematoxylin-eosin staining for histological alterations. We found that 3-NP administration caused motor incoordination and induced oxidative stress increased but reduced free radical scavenging. Also, increased amounts of lipid peroxides caused striatal damage as shown by histopathological evaluation. Administration of L-T4 led to increased falling time in the Rotarod, but reduced the time taken in Narrow beam walking and Limb withdrawal test. Furthermore, L-T4 increased antioxidant activity, decreased lipid peroxidation and ameliorated 3-NP-induced degeneration in neurons.

The effects of green tea on cognitive impairments in the rat model of Alzheimer's disease: protection against inflammatory and oxidative damage.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a decrement in the number of synapses, an increment in the production of oxygen free radicals and inflammatory cytokines. Green tea (GT) plays a defensive performance in different neurodegenerative conditions, such as cognition deficit. This study investigated the neuroprotective effect of green tea (GT) on cognitive disorder, inflammation, and oxidative stress in the streptozotocin (STZ)- induced AD model. MATERIALS AND METHODS: The rats were divided into four groups: (1) Control, (2) GT, (3) Alz, and (4) GT + Alz. AD was induced by the injection of STZ (3 mg/kg, bilaterally, ICV). Morris water maze and passive avoidance tests were done to evaluate the memory and learning of rats. Biochemical parameters were measured with specialized ELISA kits. RESULTS: Briefly, data analysis revealed that GT administration for 21 days improved memory impairment induced by the injection of STZ. Pretreatment with GT enhanced time spent in the goal quarter and reduced latency time and path length. Furthermore, pretreatment with GT prevented the increment of malondialdehyde (MDA) concentration in STZ-treated rats. As a pro-inflammatory cytokine, tumor necrosis factor- α (TNF-α) concentration was suppressed with the GT pretreatment. Total antioxidant capacity was increased after GT administration in rats treated compared with AD rats. CONCLUSIONS: GT pretreatment attenuated STZ-induced learning and memory impairment through the suppression of TNF-α and MDA concentrations. The beneficial effects of GT on memory could be attributed to its protective effects on oxidative defenses.

Effects of quercetin on spatial memory, hippocampal antioxidant defense and BDNF concentration in a rat model of Parkinson's disease: An electrophysiological study.

OBJECTIVE: Quercetin is one of the most popular flavonoid with protective effects against neural damages in Parkinson's disease (PD). We assessed the effect of quercetin administration on memory and motor function, hippocampal oxidative stress and brain-derived neurotrophic factor (BDNF) level in a 6-OHDA-induced Parkinson's rat model. MATERIAL AND METHODS: The animals were divided into the following five groups (n=8): control, sham-surgery (sham), lesion (PD), and lesion animals treated with quercetin at doses of 10 (Q10) and 25 (Q25) mg/kg. For induction of a model of PD, 6-OHDA was injected into the striatum of rats. The effects of quercetin were investigated on spatial memory, hippocampal BDNF and malondialdehyde (MDA) levels, and total antioxidant capacity (TAC). Spatial memory was assessed by Morris water maze test, and the neuronal firing frequency in hippocampal dentate gyrus (HDG) was evaluated by single-unit recordings. RESULTS: Mean path length and latency time, rotational behavior and hippocampal MDA concentration were significantly increased, while time spent in the goal quadrant, swimming speed, spike rate, and hippocampal levels of TAC and BDNF were significantly decreased in the PD group compared to the sham group (p<0.01 to p<0.001). Quercetin treatment significantly enhanced time spent in goal quadrant (p<0.05), swimming speed (p<0.001) and spike rate (p<0.01), improved hippocampal TAC (p<0.05 to p<0.001) and BDNF (p<0.01 to p<0.001) level, and decreased mean path length (p<0.001), latency time (p<0.05 to p<0.001), rotational behavior and hippocampal MDA concentration (p<0.05). CONCLUSION: The cognitive-enhancing effect of quercetin might be due to its antioxidant effects in the hippocampus.

Evaluation of the effects of metformin as adenosine monophosphate-activated protein kinase activator on spatial learning and memory in a rat model of multiple sclerosis disease.

In patients with multiple sclerosis (MS) disease, cognitive deficits have been detected because of destruction of hippocampus. Cognitive impairment is one of the common signs in MS. Recent studies showed that metformin (Met) has wide-ranging effects in the treatment of diseases. Here, we have tried to study the preservative effects of Met as adenosine monophosphate-activated protein kinase (AMPK) activator on the hippocampus dentate gyrus (DG) neuronal firing pattern, motor coordination, and learning & memory loss following MS induction. The MS induction was done by local ethidium bromide (EB) injection into the rat hippocampus. Then, rats were treated with Met (200 mg/kg) for two weeks. Spatial memory and learning status were assessed using Morris water maze. A neuronal single-unit recording was measured from hippocampus DG. After decapitation, the bilateral hippocampi separated to measure malondialdehyde (MDA). Treatment with Met ameliorated latency times and path lengths (P < 0.05, P < 0.01, P < 0.001 in 1th, 2th, 3th and 4th days) in the Met + MS group respectively. The percent of total time spent in goal quarter and the average number of spikes/bin were decreased significantly in MS rats compared with the sham group (p < 0.001) but significantly increased in the metformin-treated MS group (Met + MS), (p < 0.01, p < 0.001). Met treatment in rats with MS significantly reduced the concentration of MDA, which is an indicator of lipid peroxidation compared to untreated groups. These observations show that increase of neuronal activity, sensory-motor coordination, and improvement of spatial memory in MS rats treated with Met appears via an increment of AMPK.

Zinc supplementation is associated with a reduction in serum markers of inflammation and oxidative stress in adults: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Zinc (Zn) is a trace metal that is considered to have an impact on chronic inflammation. However, findings of clinical trials have been inconsistent. The present systematic review and meta-analysis aimed to provide a more robust examination of the evidence on the effectiveness of Zn supplements on markers of inflammation and oxidative stress. METHODS: A systematic search in PubMed, Scopus, Web of Science and Cochrane Library was undertaken to identify relevant randomized controlled trials (RCTs) assessing the impact of Zn on inflammation and oxidative stress until 17 August 2020. We applied a random-effects method to obtain effect sizes (ES) and 95% confidence intervals (CIs). Meta-regression was used to detect the potential source of between-study heterogeneity. RESULTS: Twenty-one eligible RCTs comprising 1321 participants were included in the meta-analysis. In comparison with the control groups, serum C-reactive protein (CRP) (ES = -0.92 mg/L, 95% CI = [-1.36, -0.48], P < 0.001, I2 = 90.2%), tumor necrosis factor-alpha (TNF-α) (ES = -0.49 pg/mL, 95% CI = [-084, -0.14], P = 0.006, I2 = 34.6%) and malondialdehyde (MDA) (ES = -0.42, 95% CI = [-083, -0.01], P = 0.04, I2 = 76.1%) were significantly reduced in the groups receiving Zn. Serum interleukin 6 (ES = -1.02 pg/mL, 95% CI = [-2.06, 0.02], P = 0.05, I2 = 92.3%) was marginally reduced following Zn supplementation. Moreover, treatment duration was found as the source of inter-study heterogeneity. CONCLUSION: This meta-analysis suggests that Zn supplements reduce serum concentrations of markers of inflammation and oxidation: CRP, TNF-α and MDA.

Role of crocin in several cancer cell lines: An updated review.

Cancer is a major public health problem worldwide. The most important considerable features of cancer cells are uncontrolled proliferation, up-regulated differentiation, and immortality. Crocin, as a bioactive compound of saffron and as a water-soluble carotenoid has radical scavenging, anti-hyperlipidemia, memory improving, and inhibition of tumor growth effects. The present review was designed to evaluate molecular mechanisms underlying crocin effects against cancer cell lines. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database from 1982 to 2019. According to various literature, crocin inhibits tumor growth, and its spread in several types of cancer including colorectal, pancreatic, breast, and prostate, as well as chronic myelogenous and leukemia. It inhibits telomerase activity, microtubule polymerization, cyclin D1, nuclear factor kappa B (NF-kB), multidrug resistance-associated protein (MRP1), and MRP2 overexpression. Crocin can induce apoptosis through activation of caspase 8, up-regulation of p53 expression, Bax/Bcl-2 ratio, and down-regulation expression of Bcl-2, survivin, and cyclin D1. It also down-regulates matrix metalloproteinase 2 and 9 (MMP2 and MMP9), N-cadherin, and beta-catenin expression, which are involved in tumor invasion and metastasis. Tumor invasion was also inhibited by crocin through increasing E-cadherin expression, cell cycle suppression at G1, G0/G1, S, and G2/M phases. Crocin has therapeutic and preventive effects on cancer cells line. Therefore, it has been suggested that this agent can be administered in patients that suffer from this problem.

Neuroprotective effects of gallic acid in a rat model of traumatic brain injury: behavioral, electrophysiological, and molecular studies.

OBJECTIVES: Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities. Clinically, it is essential to limit the development of cognitive impairment after TBI. In the present study, the neuroprotective effects of gallic acid (GA) on neurological score, memory, long-term potentiation (LTP) from hippocampal dentate gyrus (hDG), brain lipid peroxidation and cytokines after TBI were evaluated. MATERIALS AND METHODS: Seventy-two adult male Wistar rats divided randomly into three groups with 24 in each: Veh + Sham, Veh + TBI and GA + TBI (GA; 100 mg/kg, PO for 7 days before TBI induction). Brain injury was made by Marmarou's method. Briefly, a 200 g weight was fallen down from a 2 m height through a free-falling tube onto the head of anesthetized animal. RESULTS: Veterinary coma scores (VCS), memory and recorded hDG -LTP significantly reduced in Veh + TBI group at 1 and 24 hr after TBI when compared to Veh + Sham (P<0.001), respectively, while brain tissue content of interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) were increased significantly (P<0.001). Pretreatment of TBI rats with GA improved clinical signs, memory and hDG-LTP significantly (P<0.001) compared to Veh + TBI group, while brain tissue content of IL-1ß, IL-6, TNF-α and MDA were decreased significantly (P<0.001). CONCLUSION: Our results propose that GA has neuroprotective effect on memory and LTP impairment due to TBI through decrement of brain lipid peroxidation and cerebral pro-inflammatory cytokines.

Diosmin is neuroprotective in a rat model of scopolamine-induced cognitive impairment.

OBJECTIVE: Scopolamine, a muscarinic cholinergic receptor antagonist, is used as a standard pharmaceutical model for inducing cognitive impairment in animals. Several cognitive behaviors, such as motor function, anxiety, short-term memory, attention are affected by injections of scopolamine. In this study, we have assessed the effects of administration of the diosmin (DM, 50 and 100 mg/kg), before injection of 0.4 mg/kg of scopolamine on memory and motor function, the hippocampal dentate gyrus (DG) electrophysiological activity as well as brain inflammation. METHODS: Eighty male rats were randomly divided into five groups (Control, Veh + scopolamine, DM (50) + scopolamine and DM (100) + scopolamine, donepezil (DP) + scopolamine, n = 16). Scopolamine (0.4 mg/kg, i.p.) is used, in order to induce an animal model of cognitive impairment. Rats pretreated with doses of 50 and 100 mg/kg of DM, 3 mg/kg of DP and/or normal saline for 7 days, before injection of scopolamine. Long-term potentiation (LTP) recording was done for electrophysiological activity assessment. Passive avoidance task (PAT), rotarod and spatial memory tests were evaluated, using a shuttle box, rotarod apparatus and Morris water maze (MWM), respectively. RESULTS: Results indicated that DM at doses of 50 and 100 mg/kg, significantly reversed the LTP (amplitude and slope) impairment of the hippocampal DG neurons, induced by scopolamine. Also, DM at doses of 50 and 100 mg/kg increased the percent of the total time that animals spent in goal quarter, the step-through latency (s) and bar latency time in an animal model of cognitive impairment (p < 0.01 and p < 0.001), respectively. The concentrations of TNF-α in hippocampus of the DM and donepezil groups was significantly lower than the Veh + scopolamine group (p < 0.01). CONCLUSION: This study revealed that the DM is effective in preventing the disruption of synaptic plasticity and cognitive impairments, induced by scopolamine. The positive effects of DM may be mediated through a decline in the TNF- α concentrations in hippocampus as a pro-inflammatory cytokine. Thus, the acquired results suggested that the DM can be used, as a useful and suitable agent for memory restoration, in the treatment of dementia, seen in elderlies.

Diosmin improved cognitive deficit and amplified brain electrical activity in the rat model of traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities in humans. Clinically, it is essential to limit the progress of cognitive impairment after TBI. It is reported that diosmin has a neuroprotective effect that can limit the progress of the impairment. The aim of this study was to evaluate the effects of diosmin on neurological score, memory, tumor necrosis factor-α (TNF-α) level and long-term potentiation in hippocampal dentate gyrus after the injury. METHODS: A total of ninety six adult male Wistar rats were used as test subjects in this study. The animals were randomly assigned into one of the following three groups (n=32/group): Sham, TBI and diosmin (100mg/kg, p.o for seven consecutive days before TBI induction). TBI was induced into the animals by Marmarou's method. Briefly, a 200g weight was dropped from a 1m height through a free-falling tube onto the head of the anesthetized rats. RESULTS: The veterinary coma scale scores, memory and long-term potentiation in TBI group showed significant decrease at different times after the onset of TBI when compared with Sham (p<0.001). The TNF-α level in the hippocampus of the TBI group of animals was significantly higher than that found in the test subjects from the Sham group (p<0.001). The pre-treatment of the TBI group with diosmin significantly improved their neurological scores, memory and long-term potentiation (p<0.001) when compared with the TBI group. The TNF-α level in hippocampus of the diosmin group was significantly lower than the TBI group (p<0.001). CONCLUSION: Based on the results of the present study, pre-treatment with diosmin has protective effects against TBI-induced memory and long-term potentiation impairment. The effects of diosmin may be mediated through a decrement in the TNF-α concentration of hippocampus as a pro-inflammatory cytokine.

Beneficial effects of ellagic acid against animal models of scopolamine- and diazepam-induced cognitive impairments.

Context In a previous study, it has been shown that ellagic acid (EA), a polyphenolic compound found in pomegranate and different berries, prevents cognitive and hippocampal long-term potentiation (LTP) impairments induced by traumatic brain injury in rats through antioxidant and anti-inflammatory mechanisms. Objective The present study was conducted to assess the potential of EA as a memory enhancer. Materials and methods The elevated plus maze (EPM) and passive avoidance (PA) paradigm were used to evaluate learning and memory parameters. Three doses (10, 30 and 100 mg/kg, i.p.) of EA were administered to animals. Memory impairment was induced by scopolamine treatment (0.4 mg/kg, i.p.) and/or diazepam (1 mg/kg, i.p.). Acquisition trials were carried out 30 min after scopolamine treatment and retention trials were performed for 5 min 24 h after the acquisition trials. Results EA at doses 30 and 100 mg/kg significantly reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) in the EPM and PA tests in mice. Also, EA at doses 30 and 100 mg/kg significantly antagonized the amnesia induced by diazepam (1 mg/kg, i.p.) in EPM test in rats. Moreover, chronic administration of EA at dose 30 mg/kg ameliorated the memory deficit induced by diazepam (1 mg/kg, i.p.) in rats. Discussion and conclusion This study demonstrates that ellagic acid is effective in preventing scopolamine- and diazepam-induced cognitive impairments without altering the animals' locomotion. This suggests the potential of EA application as a useful memory restorative agent in the treatment of dementia seen in elderly persons.

Gallic acid improved behavior, brain electrophysiology, and inflammation in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities. In the clinic it is essential to limit the development of cognitive impairment after TBI. In this study, the effects of gallic acid (GA; 100 mg/kg, per oral, from 7 days before to 2 days after TBI induction) on neurological score, passive avoidance memory, long-term potentiation (LTP) deficits, and levels of proinflammatory cytokines including interleukin-1 beta (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in the brain have been evaluated. Brain injury was induced following Marmarou's method. Data were analyzed by one-way and repeated measures ANOVA followed by Tukey's post-hoc test. The results indicated that memory was significantly impaired (p < 0.001) in the group treated with TBI + vehicle, together with deterioration of the hippocampal LTP and increased brain tissue levels of IL-1ß, IL-6, and TNF-α. GA treatment significantly improved memory and LTP in the TBI rats. The brain tissue levels of IL-1ß, IL-6, and TNF-α were significantly reduced (p < 0.001) in the group treated with GA. The results suggest that GA has neuroprotective properties against TBI-induced behavioral, electrophysiological, and inflammatory disorders, probably via the decrease of cerebral proinflammatory cytokines.