Administration of growth hormone ameliorates adverse effects of total sleep deprivation.

Total sleep deprivation (TSD) causes several harmful changes including anxiety, inflammation, and increased expression of extracellular signal-regulated kinase (ERK) and tropomyosin receptor kinase B (TrkB) genes in the hippocampus. The current study was conducted to explain the possible effects of exogenous GH against the above parameters caused by TSD and the possible mechanisms involved. Male Wistar rats were divided into 1) control, 2) TSD and 3) TSD + GH groups. To induce TSD, the rats received a mild repetitive electric shock (2 mA, 3 s) to their paws every 10 min for 21 days. Rats in the third group received GH (1 ml/kg, sc) for 21 days as treatment for TSD. The motor coordination, locomotion, the level of IL-6, and expression of ERK and TrkB genes in hippocampal tissue were measured after TSD. The motor coordination (p < 0.001) and locomotion indices (p < 0.001) were impaired significantly by TSD. The concentrations of serum corticotropin-releasing hormone (CRH) (p < 0.001) and hippocampal interleukin-6 (IL-6) (p < 0.001) increased. However, there was a significant decrease in the interleukin-4 (IL-4) concentration and expression of ERK (p < 0.001) and TrkB (p < 0.001) genes in the hippocampus of rats with TSD. Treatment of TSD rats with GH improved motor balance (p < 0.001) and locomotion (p < 0.001), decreased serum CRH (p < 0.001), IL-6 (p < 0.01) but increased the IL-4 and expression of ERK (p < 0.001) and TrkB (p < 0.001) genes in the hippocampus. Results show that GH plays a key role in modulating the stress hormone, inflammation, and the expression of ERK and TrkB genes in the hippocampus following stress during TSD.

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.

The effects of gallic acid and vagotomy on motor function, intestinal transit, brain electrophysiology and oxidative stress alterations in a rat model of Parkinson's disease induced by rotenone.

INTRODUCTION: The neuropathology of Parkinson's disease (PD) is complex and affects multiple systems of the body beyond the central nervous system. This study examined the effects of gallic acid (GA) and gastrointestinal vagotomy (VG) on motor, cognitive, intestinal transit time, and thalamic nuclei electrical power in an animal model of PD induced by rotenone. MATERIALS AND METHODS: Male Wistar rats were divided into 4 groups: Sham, ROT, ROT+GA, VG + ROT. Sham rats received vehicle, those in ROT received rotenone (5 mg/kg/2 ml, ig), PD rats in ROT+GA were treated with GA (100 mg/kg, gavage/once daily, for 28 days), and in VG + ROT, the vagal nerve was dissected. Stride length, motor coordination and locomotion, intestinal transit time, cognitive and pain threshold, and thalamic local EEG were evaluated. Oxidative stress indexes in striatal tissue were also measured. RESULTS: Rotenone diminished significantly the stride length (p < 0.001), motor coordination (p < 0.001), power of thalamic EEG (p < 0.01) and pain (p < 0.001). MDA increased significantly (p < 0.001) while GPx activity decreased (p < 0.001). Intestinal transit time rose significantly (p < 0.01). PD rats treated with GA improved all above disorders (p < 0.001, p < 0.01). Vagotomy prevented significant alterations of motor and non-motor parameters by rotenone. CONCLUSION: According to current findings, rotenone acts as a toxin in GI and plays a role in the pathogenesis of PD through gastric vagal nerve. Thus, vagotomy could prevent the severity of toxicity by rotenone. In addition, GA improved symptoms of PD induced by rotenone. Therefore, GA can be regarded as a promising therapeutic candidate for PD patients.

Neuroprotective effects of Wharton's jelly-derived mesenchymal stem cells on motor deficits due to Parkinson's disease.

OBJECTIVES: Human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) have been recognized as a potential tool to replace damaged cells by improving the survival of the dopaminergic cells in Parkinson's disease (PD). In this study, we examined the effects of hWJ-MSCs and associated with L-dopa/carbidopa on motor disturbances in the PD model. MATERIALS AND METHODS: PD was induced by injection of 6-hydroxydopamine (6-OHDA) (16 µg/2 µl into medial forebrain bundle (MFB)). Sham group received a vehicle instead of 6-OHDA. PD+C group received hWJ-MSCs twice on the 14th and 28th days post PD induction. PD+C+D group received hWJ-MSCs and also L-dopa/carbidopa (10/30 mg/kg). PD+D group received L-dopa/carbidopa alone. Four months later, motor activities (the parameters of locomotor and muscle stiffness) were evaluated, dopaminergic neurons were counted in substantia nigra pars compacta (SNc), the level of dopamine (DA), and tyrosine hydroxylase (TH) were measured in the striatum. RESULTS: Data indicated that motor activities, the number of dopaminergic neurons, and levels of DA and TH activities were significantly reduced in PD rats as compared to the sham group (P<0.001). However, the same parameters were improved in the treated groups when compared with the PD group (P<0.001 and P<0.01, respectively). CONCLUSION: The chronic treatment of PD rats with hWJ-MSCs and L-dopa/carbidopa, improved motor activity, which may be the result of increased TH activity and due to released DA from dopaminergic neurons.

Therapeutic effects of Wharton's jelly-derived Mesenchymal Stromal Cells on behaviors, EEG changes and NGF-1 in rat model of the Parkinson's disease.

Human Wharton's jelly-derived Mesenchymal Stromal Cells (hWJ-MSCs) have shown beneficial effects in improving the dopaminergic cells in the Parkinson's disease (PD). In the present study, the effects of hWJ-MSCs on hyperalgesia, anxiety deficiency and Pallidal local electroencephalogram (EEG) impairment, alone and combined with L-dopa, were examined in a rat model of PD. Adult male Wistar rats were divided into five groups: 1) sham, 2) PD, 3) PD + C (Cell therapy), 4) PD + C+D (Drug), and 5) PD + D. PD was induced by injection of 6-OHDA (16 µg/2 µl into medial forebrain bundle (MFB)). PD + C group received hWJ-MSCs (1 × 106 cells, intravenous (i.v.)) twice post PD induction. PD + C+D groups received hWJ-MSCs combined with L-Dopa/Carbidopa, (10/30 mg/kg, intraperitoneally (i.p.)). PD + D group received L-Dopa/Carbidopa alone. Four months later, analgesia, anxiety-like behaviors, were evaluated and Pallidal local EEG was recorded. Level of insulin-like growth factor 1 (IGF-1) was measured in the striatum and dopaminergic neurons were counted in substantia nigra (SNc). According to data, MFB-lesioned rats showed hyperalgesia in tail flick, anxiety-like symptoms in cognitive tests, impairment of electrical power of pallidal local EEG as field potential, count of dopaminergic neurons in SNc and level of IGF-1 in striatum. These complications restored significantly by MSCs treatment (p < 0.001). Our findings confirm that chronic treatment with hWJ-MSC, alone and in combination with L-Dopa, improved nociception and cognitive deficit in PD rats which may be the result of increasing IGF-1 and protect the viability of dopaminergic neurons.

Transplanted Wharton's jelly mesenchymal stem cells improve memory and brain hippocampal electrophysiology in rat model of Parkinson's disease.

BACKGROUND: Experimental findings have shown that stem cell transplantation is a therapeutic procedure for Parkinson's disease (PD). In this study, effects of human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs), alone and combined with l-dopa, were examined for repairing memory impairment in a rat model of PD. METHODS: Fifty adult male Wistar rats were randomly divided into five groups: 1) sham, 2) PD, 3) PD + C, 4) PD + C+D, and 5) PD + D. PD was induced by 6-OHDA injection (16 µg/2 µl) into medial forebrain bundle (MFB) and was confirmed 14 days later by contralateral rotation using apomorphine injection. The rats received hWJ-MSCs (1 × 106 cells, i.v.) twice on the 14th and 28th days post PD induction. Treated PD rats received hWJ-MSCs alone or combined with l-Dopa and Carbidopa (10/30 mg/kg, i.p.). Four months later, memory, hippocampal long-term potentiation (hLTP), histological changes, and the levels of BDNF and NGF in striatum were evaluated. RESULTS: PD caused both cell loss with small dark stained nuclei in granular zone as well as significant decrement of BDNF and NGF (P < 0.001) in striatum. These pathological alterations were associated with memory and hLTP deficits (P < 0.001 respectively). Treating PD rats with hWJ-MSCs, alone (P < 0.05 and P < 0.001) and combined with l-Dopa (P < 0.001), significantly restored the levels of both of the neurotrophins followed by improving cognition and hLTP (P < 0.001). CONCLUSION: Current findings showed that chronic treatment of PD rats with hWJ-MSCs, alone and in combination with l-Dopa, could restore memory and hLTP by reconstructing dopaminergic neurons and elevating the BDNF and NGF factors.

Ellagic Acid Protects Cardiac Arrhythmias Following Global Cerebral Ischemia/Reperfusion Model.

BACKGROUND: Cerebral ischemia/reperfusion (I/R) could increase the reactive oxidative stress in the cardiomyocytes. Also, some studies report cardiac arrhythmias following oxidative stressor such as I/R. Hence, this study was aimed to investigate the effects of ellagic acid (EA) against arrhythmias in a cerebral I/R model. MATERIALS AND METHODS: Thirty-two male rats were randomly allocated into four groups: Sham (normal saline, 10 days), EA (100 mg/kg EA, 10 days), I/R (20 min ischemia followed by 30 min reperfusion, 10 days), and EA + I/R (100 mg/kg EA before I/R). In all animals, electrocardiogram (ECG) was recorded pre-ischemia and postischemia on the first and 11th days, respectively. RESULTS: The I/R group showed an abnormally prolonged QTc interval after ischemia compared to the preischemia and control groups. EA administration in the EA+I/R group significantly reduced this prolonged QTc interval (P< 0.01). In the I/R group, ischemic/reperfusion resulted in a prolonged QRS complex and an elevated ST, which EA significantly prevented (P<0.01). In addition, EA significantly prevented the dramatically shortened RR interval induced by reperfusion (P<0.01). The incidence of ventricular fibrillation significantly increased in the I/R group; then it dramatically decreased following the administration of EA (P<0.0001). CONCLUSION: EA pretreatment repaired the adverse effects of I/R on the ECG parameters, which can be attributed to its negative chronotropic effects. EA pretreatment can prevent the cerebral I/R-induced heart arrhythmias.

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.

Therapeutic effects of ellagic acid on memory, hippocampus electrophysiology deficits, and elevated TNF-α level in brain due to experimental traumatic brain injury.

OBJECTIVES: Cognitive defects such as learning and memory impairment are amongst the most repetitious sequelae after sever and moderate traumatic brain injury (TBI). It was suggested that ellagic acid (EA), an innate phenol product, display neuroprotective properties against oxidative and inflammatory damages after brain injury. The object of the current study was therapeutic properties of EA on blood-brain barrier (BBB) interruption and elevated content of TNF-α in brain tissue followed by neurologic aftereffects, cognitive and brain electrophysiology deficits as outcomes of diffuse TBI in rat. MATERIALS AND METHODS: TBI was induced by a 200 g weight falling by a 2-m height through a free-falling tube onto the head of anesthetized rat. TBI rats treated immediately after trauma with EA (100 mg/kg, IP) once every 8 hr until 48 hr later. Neurologic outcomes, passive avoidance task (PAT), hippocampal long-term potentiation (LTP), BBB permeability and content of TNF-α in brain tissue were evaluated. RESULTS: TBI induced significant impairments in neurological score, BBB function, PAT and hippocampal LTP in TBI+Veh group in compare with Sham+Veh (P<0.001). EA treatment decreased neurologic severity score (NSS), restored increased BBB permeability, cognitive and hippocampal LTP abnormalities, and elevated brain content of TNF-α due to TBI significantly (P<0.001). CONCLUSION: Our findings propose that EA can restore NSS, cognitive and LTP deficits and prevent brain inflammation may by restore BBB permeability as well as lowering brain content of TNF-α following TBI.

Effects of ellagic acid pretreatment on renal functions disturbances induced by global cerebral ischemic-reperfusion in rat.

OBJECTIVES: Global cerebral ischemia-reperfusion (GCIR) causes disturbances in brain functions as well as other organs such as kidney. Our aim was to evaluate the protective effects of ellagic acid (EA) on certain renal disfunction after GCIR. MATERIALS AND METHODS: Adult male Wistar rats (n=32, 250-300 g) were used. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). Animal groups were: 1) received DMSO/saline (10%) as solvent of EA, 2) solvent + GCIR, 3) EA + GCIR, and 4) EA. Under anesthesia with ketamine/xylazine, GCIR was induced (20 and 30 min respectively) in related groups. EA (100 mg/kg, dissolved in DMSO/saline (10%) or solvent was administered (1.5 ml/kg) orally for 10 consecutive days to the related groups. EEG was recorded from NTS in GCIR treated groups. RESULTS: Our data showed that: a) EEG in GCIR treated groups was flattened. b) GCIR reduced GFR (P<0.01) and pretreatment with EA attenuated this reduction. c) BUN was increased by GCIR (P<0.001) and pretreatment with EA improved the BUN to normal level. d) Serum creatinine concentration was elevated by GCIR but not significantly, however, in EA+GCIR group serum creatinine was reduced (P<0.05). e) GCIR induced proteinuria (P<0.05) but, EA was unable to reduced proteinuria. CONCLUSION: Results indicate that GCIR impairs certain renal functions and EA as an antioxidant can improve these functions. Our results suggest the possible usefulness of ellagic acid in patients with brain stroke.

Ellagic acid improved arrhythmias induced by CaCL2 in the rat stress model.

OBJECTIVE: In ventricular arrhythmias, due to their free radical scavenging action, antioxidant agents are usually used in the treatment of cardiovascular disease. Since stress is considered as risk factor for increased mortality by causing malignant arrhythmias, the study was designed to evaluate the cardioprotective effects of ellagic acid (EA) on CaCl2-induced arrhythmias in rat stress model. MATERIALS AND METHODS: Male Sprague-Dawley rats (200-250 g) were divided into four groups: Group I: Control rats (2 ml of saline by gavage), Group II: Rats treated with EA (15 mg/kg, gavage), Group III: stress group, Group IV: received EA plus stress. Stress was applied in a restrainer box (6 hour/day, 21 days). After induction of anesthesia, lead II electrocardiogram was recorded for calculating heart rate and QRS complex. The arrhythmia was produced by injection of CaCl2 solution (140 mg/kg, iv) and incidences of Ventricular fibrillation, Ventricular premature beats and Ventricular tachycardia were recorded. Results were analyzed by using one-way ANOVA and Fisher`s exact test. p<0.05 was considered as significant level. RESULTS: The results showed a positive inotropic effect and negative chronotropic effect for the EA group in comparison with the control group. Incidence rates (%) of premature beats, ventricular fibrillation and ventricular tachycardia in stress group and all the arrhythmia parameters decreased in groups which received EA. CONCLUSIONS: By decreasing the incidence rates of premature beats, fibrillation and ventricular tachycardia in groups which received EA, ellagic acid probably acted as an anti-arrhythmic agent which showed to have aprotective functionin heart.

Pomegranate seed hydroalcoholic extract improves memory deficits in ovariectomized rats with permanent cerebral hypoperfusion /ischemia.

OBJECTIVES: Estrogen deficit following menopause results in cognitive behaviors impairment. This study aimed to evaluate the effects of pomegranate seed extract (PGSE) on avoidance memories after permanent bilateral common carotid arteries occlusion (2CCAO) in ovariectomized (OVX) rats. MATERIALS AND METHODS: Adult female Wistar rats were divided randomly into eight groups with 8 rats in each group: 1) Sham-operated for ovaries and 2CCAO (ShO); 2) OVX and sham operated for ischemia (OShI); 3-7) OVX with 2CCAO (OI) received PGSE (100, 200, 400 and 800 mg/2ml/kg or normal saline, orally) for 14 days (OI+E100, 200, 400, 800 or OI+Veh); 8) OShI received most effective dose of PGSE (200 and 400 mg/kg for passive and active avoidance memories respectively). Active and passive avoidance tasks were measured in Y-maze and two-way shuttle box respectively. Data were analyzed with one-way and RM-ANOVA followed by HSD post-hoc test. RESULTS: Sensorimotor impaired in OShI+Veh and OI+Veh (P<0.001 vs. ShO). PGSE improved it significantly in dose dependently manner (P<0.001 vs. OI+Veh). Both types of memories were significantly impaired in OVX rats before and after 2CCAO (P<0.001). PGSE treatment significantly improved memories in OI groups (P<0.05, P<0.01 and P<0.001) compared with OI+Veh. No toxicity was observed with PGSE consumption (800 mg/kg, 2 weeks, orally). CONCLUSION: PGSE exhibits therapeutic potential for avoidance memories, which is most likely related at least in part to its phytoestrogenic and also antioxidative actions.

Ellagic acid improves electrocardiogram waves and blood pressure against global cerebral ischemia rat experimental models.

BACKGROUND: Global cerebral ischemia (GCIR) arises in patients that are shown a variety of clinical difficulty including cardiac arrest, asphyxia, and shock. In spite of advances in understanding of the brain, ischemia and protective effects to improve ischemic injury still remain unknown. The aim of our study was to investigate the effect of ellagic acid (EA) pretreatment in the rat models of global cerebral ischemia reperfusion. METHODS: This experimental study was conducted in 2014 at the Physiology Research Center of the Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran. Adult male Wistar rats (250-300 g) were used in this study. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). 32 rats were divided randomly to four groups: 1) So (Sham) received normal saline as vehicle of EA, 2) EA, 3) normal saline + GCIR, and 4) EA + GCIR. After anesthesia (a mix of xylazine and ketamine), animal subjected to 20 minutes of ischemia followed by 30 minutes of reperfusion in related groups. EA (100 mg/kg, dissolved in normal saline) or 1.5 ml/kg normal saline was administered (gavage, 10 days) to the related groups. EEG was recorded from NTS in GCIR treated groups. RESULTS: Present data showed that: 1) EEG in GCIR treated groups was flattened; 2) Blood pressure, voltage of QRS and P-R interval were reduced significantly in the ischemic groups compared to before ischemia, and pretreatment with EA prevented this reduction; and 3) MDA level and heart rate was increased by GCIR and pretreatment with EA reduced MDA level and restored the HR to normal level. CONCLUSION: Results indicate that global cerebral ischemia-reperfusion impairs certain heart functions and ellagic acid as an antioxidant can restore these parameters. The results of this study suggest the possible utility of ellagic acid in patients with brain stroke.

A possible mechanism for the anxiolytic-like effect of gallic acid in the rat elevated plus maze.

This work was performed to characterize the possible mechanisms involved in the anxiolytic-like activity of gallic acid (GA) in the rat elevated plus maze (EPM) test. Male Wistar rats were acutely treated with a single dose of GA (10-500 mg/kg, i.p.) or diazepam and buspirone, 30 min prior to behavioral assessment in the EPM, open-field and rotarod tests. Treatment with GA markedly produced an increase in the time spent and entries in the open arms of EPM at doses of 30 and 300 mg/kg, respectively. These effects were comparable to those of the diazepam (1 mg/kg, i.p.) and buspirone (1 mg/kg, i.p.). Pretreatment with benzodiazepine antagonist flumazenil (3 mg/kg, i.p.) partially blocked the anxiolytic-like effect of GA. However, an increase in the time spent and entries in the open arms of EPM observed with GA treatment were significantly inhibited by the 5-HT1A receptor antagonist WAY-100635 (0.5 mg/kg, i.p.). In the open-field test, only GA at a dose of 500 mg/kg decreased locomotor activity in rats. Moreover, GA (10-300 mg/kg, i.p.) or diazepam and buspirone did not alter motor coordination in the rotarod test. These results indicate that GA is an effective anxiolytic agent at low doses, while at the highest dose it has sedative effect. Also this study suggests that the anxiolytic-like activity of GA is primarily mediated by the 5-HT1A but not benzodiazepine receptors.

Protective effects of gallic acid against chronic cerebral hypoperfusion-induced cognitive deficit and brain oxidative damage in rats.

Free radical-induced neural damage is implicated in cerebral hypoperfusion disorders and antioxidants have protective effects. In the present study, we examined the effect of gallic acid (GA; 100mg/kg, p.o. for 10 days) on cognitive deficit and cerebral oxidative stress induced by permanent bilateral common carotid artery occlusion (2VO) as an animal model of vascular dementia (VD). The results showed that 2VO significantly reduced the spatial memory performance in Morris water maze as well as non-enzymatic (total thiol) and enzymatic [glutathione peroxidase (GPx)] antioxidant contents and increased the level of malondialdehyde (MDA) in the hippocampus and frontal cortex of vehicle-treated group as compared to sham-operated rats. Furthermore, chronic administration of GA significantly restored the spatial memory, total thiol and GPx contents and also decreased MDA levels in these tissues. GA alone did not show any change neither in the status of various antioxidants nor behavioral tests over sham values. The results demonstrate that GA has beneficial activity against 2VO-induced cognitive deficits via enhancement of cerebral antioxidant defense. Taken together, the present study suggested that GA might be useful in the treatment of VD.

Agmatine protects against intracerebroventricular streptozotocin-induced water maze memory deficit, hippocampal apoptosis and Akt/GSK3ß signaling disruption.

Centrally administered streptozotocin (STZ), is known to cause Alzheimer׳s like memory deterioration. It mainly affects insulin signaling pathways such as PI3/Akt and GSK-3ß which are involved in cell survival. Previous studies indicate that STZ increases the ratio of Bax/Bcl-2 and thereby induces caspase-3 activation and apoptosis. Agmatine, a polyamine derived from l-arginine decarboxylation, is recently shown to exert some neuroprotective effects. This study aimed to assess if agmatine reverses STZ-induced memory deficits, hippocampal Akt/GSK-3ß signaling disruption and caspase-3 activation. Adult male Sprague-Dawely rats weighing 200-250 g were used. The canules were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3 mg/kg) and agmatine treatment (40 or 80 mg/kg) was started from day 4 and continued in an every other day manner till day 14. The animal׳s learning and memory capability was assessed on days 15-18 using Morris water maze. After complement of behavioral studies the hippocampi was isolated and the amounts of hippocampal cleaved caspase-3 (the landmark of apoptosis), Bax/Bcl-2 ratio, total and phosphorylated forms of GSK-3ß and Akt were analyzed by western blot. The results showed that agmatine in 80 but not 40 mg/kg reversed the memory deterioration induced by STZ. Western blot analysis revealed that STZ prompted elevation of caspase-3; Bax/Bcl-2 ratio and disrupted Akt/GSK-3ß signaling in the hippocampus. Agmatine treatment prevented apoptosis and Akt/GSK-3ß signaling impairment induced by STZ. This study disclosed that agmatine treatment averts not only STZ-induced memory deterioration but also hippocampal apoptosis and Akt/GSK-3ß signaling disruption.

Central and peripheral antinociceptive effects of ellagic acid in different animal models of pain.

The present study was conducted to evaluate the analgesic effects of p.o., i.p., or i.c.v. administration of ellagic acid (EA), and investigate the possible mechanisms underlying the systemic antinociceptive activities in different animal models of pain. Using radiant heat tail-flick test, EA (100-1000 µmol/kg, retain-->p.o.) only resulted in antinociception at 1000 µmol/kg. Also, EA (10-660 µmol/kg, i.p.) produced the antinociceptive effect in a dose-dependent manner with an ED50 of 122 µmol/kg. In addition, the i.c.v. administration of EA (0.1-2 µmol/rat) resulted in dose-dependent antinociception with an ED50 of 0.33 µmol/rat. EA induced antinociception (330 µmol/kg. i.p.) was reversed by naloxone (1 mg/kg, i.p.). Likewise, EA (1-33 µmol/kg, i.p.) produced significant dose-dependent antinociception when assessed using acetic acid-induced abdominal writhing test with an ED50 of 3.5 µmol/kg. It was also demonstrated that pre-treatment with L-arginine (100mg/kg, i.p.), a nitric oxide (NO) precursor, and methylene blue (20 mg/kg, i.p.), a guanylate cyclase (GC) inhibitor, significantly enhanced antinociception produced by EA suggesting the involvement of L-arginine-NO-cGMP pathway. Additionally, administration of glibenclamide (10mg/kg, i.p.), an ATP-sensitive K(+) channel blocker, significantly reversed antinociceptive activity induced by EA. Moreover, EA treatment had no effect on the motor activity of rats when tested in rota-rod task. The present results indicate that the dose-related antinociceptive action of EA has both peripheral and central components which involve mediation by opioidergic system and L-arginine-NO-cGMP-ATP sensitive K(+) channels pathway.

Gallic acid prevents memory deficits and oxidative stress induced by intracerebroventricular injection of streptozotocin in rats.

In the present study, we evaluated the effects of gallic acid (GA; 30 mg/kg, orally, once daily for 26 days starting from day 5 prior to streptozotocin injection) on cognitive impairment and cerebral oxidative stress induced by intracerebroventricular-streptozotocin (ICV-STZ; bilaterally, two doses of 3 mg/kg) injection as an animal model of sporadic Alzheimers type (SDAT) in rats. The results showed that ICV-STZ-injection reduced the passive avoidance and spatial memory performance associated with decreased non-enzymatic [total thiol concentration, -58.5%, -50.7%] and enzymatic [superoxide dismutase (SOD, -30.2%, -32.9%), catalase (CAT, -43.5%, -50.7%), glutathione peroxidase (GPx, -57.1%, -61.7%)] activities and increased the level of thio-barbituric acid reactive species (TBARS, +103.5%, +82.5%) in the hippocampus and cerebral cortex, respectively. In contrast, chronic administration of GA significantly prevented cognitive deficits and biochemical alterations in the ICV-STZ rats. These findings highlight the beneficial role of GA in the ICV-STZ rats via enhancement of cerebral antioxidant defense system. Thus, it may have a therapeutic value for the treatment of SDAT.