Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer's disease.

BACKGROUND: Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat's model of Alzheimer's disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aß). METHODS: Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aß, 4. pretreatment (Vin + Aß): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aß(1-42), 5. treatment (Aß + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aß + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus. RESULTS: Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aß group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP). CONCLUSIONS: Vin could significantly prevent the Aß effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aß on hippocampal synaptic plasticity.

Policosanol protects against Alzheimer's disease-associated spatial cognitive decline in male rats: possible involved mechanisms.

RATIONALE: Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and synaptic failure. OBJECTIVE: The present study was designed to explore the possible protective effects of policosanol (PCO) on spatial cognitive capacity, long-term potentiation (LTP) induction, oxidant/antioxidant status, and Aß plaques formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aß1-40. METHODS: Healthy adult male Wistar rats were randomly divided into control, sham (ICV injection of 5 µl phosphate-buffered saline), AG (50 mg/kg; P.O., as PCO vehicle), PCO (50 mg/kg; P.O.), AD model (ICV injection of 5 µl Aß), AD + AG (50 mg/kg; P.O.), and AD + PCO (50 mg/kg; P.O.). Treatments were performed for eight consecutive weeks. At the end of the treatment course, spatial learning and memory functions, hippocampal long-term potentiation (LTP) induction, malondialdehyde (MDA), and total thiol group (TTG) levels, as well as the formation of Aß plaques, were examined. RESULTS: The results showed that injection of Aß reduced spatial learning and memory abilities in the Barnes maze test, which was accompanied by decreases in field excitatory postsynaptic potential (fEPSP) slope, population spike (PS) amplitude, and TTG level and increases in Aß plaque accumulation and MDA content. In contrast, PCO treatment improved all the above-mentioned changes in the Aß-infused rats. CONCLUSIONS: The results suggest that amelioration of hippocampal synaptic plasticity impairment, modulation of oxidant/antioxidant status, and inhibition of Aß plaque formation by PCO may be the mechanisms behind its protective effect against AD-associated spatial cognitive decline.

Effectiveness of coenzyme Q10 on learning and memory and synaptic plasticity impairment in an aged Aß-induced rat model of Alzheimer's disease: a behavioral, biochemical, and electrophysiological study.

RATIONALE: Aging is the major risk factor for Alzheimer's disease (AD), and cognitive and memory impairments are common among the elderly. Interestingly, coenzyme Q10 (Q10) levels decline in the brain of aging animals. Q10 is a substantial antioxidant substance, which has an important role in the mitochondria. OBJECTIVE: We assessed the possible effects of Q10 on learning and memory and synaptic plasticity in aged ß-amyloid (Aß)-induced AD rats. METHODS: In this study, 40 Wistar rats (24-36 months old; 360-450 g) were randomly assigned to four groups (n = 10 rats/group)-group I: control, group II: Aß, group III: Q10; 50 mg/kg, and group IV: Q10+Aß. Q10 was administered orally by gavage daily for 4 weeks before the Aß injection. The cognitive function and learning and memory of the rats were measured by the novel object recognition (NOR), Morris water maze (MWM), and passive avoidance learning (PAL) tests. Finally, malondialdehyde (MDA), total antioxidant capacity (TAC), total thiol group (TTG), and total oxidant status (TOS) were measured. RESULTS: Q10 improved the Aß-related decrease in the discrimination index in the NOR test, spatial learning and memory in the MWM test, passive avoidance learning and memory in the PAL test, and long-term potentiation (LTP) impairment in the hippocampal PP-DG pathway in aged rats. In addition, Aß injection significantly increased serum MDA and TOS levels. Q10, however, significantly reversed these parameters and also increased TAC and TTG levels in the Aß+Q10 group. CONCLUSIONS: Our experimental findings suggest that Q10 supplementation can suppress the progression of neurodegeneration that otherwise impairs learning and memory and reduces synaptic plasticity in our experimental animals. Therefore, similar supplemental Q10 treatment given to humans with AD could possibly provide them a better quality of life.

The Protective Effects of Policosanol on Learning and Memory Impairments in a Male Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by a progressive decline in cognitive performance and memory formation. The present study was designed to investigate the effect of policosanol (PCO) on cognitive function, oxidative-antioxidative status, and amyloid-beta (Aß) plaque formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aß1-40. Healthy adult male Wistar rats were randomly divided into seven groups: control, sham (5 µL, ICV injection of phosphate-buffered saline), AD model (5 µL, ICV injection of Aß), acacia gum (50 mg/kg, 8 weeks, gavage), PCO (50 mg/kg, 8 weeks, gavage), AD + acacia gum (50 mg/kg, 8 weeks, gavage), and AD + PCO (50 mg/kg, 8 weeks, gavage). During the ninth and tenth weeks of the study, the cognitive function of the rats was assessed by commonly used behavioral paradigms. Subsequently, oxidative-antioxidative status was examined in the serum. Moreover, compact Aß plaques were detected by Congo red staining. The results showed that injection of Aß impaired recognition memory in the novel object recognition test, reduced the spatial cognitive ability in the Morris water maze, and alleviated retention and recall capability in the passive avoidance task. Additionally, injection of Aß resulted in increased total oxidant status, decreased total antioxidant capacity, and enhanced Aß plaque formation in the rats. Intriguingly, PCO treatment improved all the above-mentioned neuropathological changes in the Aß-induced AD rats. The results suggest that PCO improves Aß-induced cognitive decline, possibly through modulation of oxidative-antioxidative status and inhibition of Aß plaque formation.

Effects of Buprenorphine on the Memory and Learning Deficit Induced by Methamphetamine Administration in Male Rats.

Little is known about the effects of methamphetamine (Meth) and buprenorphine (Bup) on memory and learning in rats. The aim of this investigation was to examine the impact of Meth and Bup on memory and learning. Fourteen male Wistar rats weighing 250-300 g were assigned to four groups: Sham, Meth, Bup, and Meth + Bup and were treated for 1 week. Spatial learning and memory, avoidance learning, and locomotion were assessed using the Morris water maze, passive avoidance learning, and open field tests, respectively. Meth and Bup impaired spatial learning and memory in rats. Co-administration of Meth + Bup did not increase the time spent in the target quadrant compared to Meth alone in the MWM. The Bup and Meh + Bup groups were found with an increase in step-through latency (STLr) and a decrease in the time spent in the dark compartment (TDC). Meth and Bup had no effects on locomotor activity in the open field test. Bup showed a beneficial effect on aversive memory. Since Bup demonstrates fewer side effects than other opioid drugs, it may be preferable for the treatment of avoidance memory deficits in patients with Meth addiction.

Effects of Hypericum scabrum extract on dentate gyrus synaptic plasticity in high fat diet-fed rats.

High-fat diet (HFD) can induce deficits in neural function, oxidative stress, and decrease hippocampal neurogenesis. Hypericum (H.) scabrum extract (Ext) contains compounds that could treat neurological disorders. This study aimed to examine the neuroprotective impacts of the H. scabrum Ext on hippocampal synaptic plasticity in rats that were fed HFD. Fifty-four male Wistar rats (220 ± 10 g) were randomly arranged in six groups: (1) HFD group; (2) HFD + Ext300 group; (3) HFD + Ext100 group; (4) Control group; (5) Ext 300 mg/kg group; (6) Ext 100 mg/kg group. These protocols were administrated for 3 months. After this stage, a stimulating electrode was implanted in the perforant pathway (PP), and a bipolar recording electrode was embedded into the dentate gyrus (DG). Long-term potentiation (LTP) was provoked by high-frequency stimulation (HFS) of the PP. Field excitatory postsynaptic potentials (EPSP) and population spikes (PS) were recorded at 5, 30, and 60 min after HFS. The HFD group exhibited a large and significant decrease in their PS amplitude and EPSP slope as compared to the control and extract groups. In reverse, H. scabrum administration in the HFD + Ext rats reversed the effect of HFD on the PS amplitude and EPSP slope. The results of the study support that H. scabrum Ext can inhibit diminished synaptic plasticity caused by the HFD. These effects are probably due to the extreme antioxidant impacts of the Ext and its capability to scavenge free radicals.

Effects of thymol on amyloid-ß-induced impairments in hippocampal synaptic plasticity in rats fed a high-fat diet.

Obesity and a high-fat diet (HFD) are known to increase the incidence of Alzheimer's disease (AD). Oxidative stress, a major risk factor for AD, is increased with HFD consumption. Thymol (Thy) has antioxidant properties. Therefore, in the present study, we examined the protective and therapeutic effects of Thy on amyloid-ß (Aß)-induced impairments in the hippocampal synaptic plasticity of HFD-fed rats. In this study, 72 adult male Wistar rats were randomly assigned to 9 groups (n = 8 rats/group): Group 1 (control; standard diet); Group 2: Control + phosphate-buffered saline (PBS) + Oil (Thy vehicle); Group 3 (HFD + PBS); Group 4: (HFD + Aß); Group 5: Control + PBS + Thy; Group 6: (HFD + Aß + Oil); Group 7: Control + Aß + Thy; Group 8: HFD + PBS + Thy; Group 9: (HFD + Aß + Thy). After stereotaxic surgery, the field potentials were recorded after the implantation of the recording and stimulating electrodes in the dentate gyrus (DG) and perforant pathway, respectively. Following high-frequency stimulation, the long-term potentiation (LTP) of the population spike (PS) amplitude and the slope of the excitatory postsynaptic potentials (EPSPs) were measured in the DG. The HFD rats that received Aß exhibited a significant decrease in their EPSP slope and PS amplitude as compared to the control group. In contrast, Thy administration in the HFD + Aß rats reduced the decrease in the EPSP slope and PS amplitude. Thy decreased the Aß-induced LTP impairments in HFD rats. The HFD significantly increased serum malondialdehyde levels and decreased total antioxidant capacity and total glutathione levels; whereas, Thy supplementation significantly reversed these parameters. Therefore, these results suggest that Thy, a natural antioxidant, can be therapeutic against high risk factors for AD, such as HFD.

Erratum to: Treadmill exercise alters ecstasy- induced long- term potentiation disruption in the hippocampus of male rats.

In the original publication of the article, author name Masoumeh Asadbegi was incorrectly written as Masoumeh Asadbeigi. The authors regret the oversight.

The effects of methamphetamine and buprenorphine, and their interaction on anxiety-like behavior and locomotion in male rats.

Methamphetamine (Meth) abuse and dependence are major global problems. Most of previous studies showed that Meth is anxiogenic. While buprenorphine (Bup) is used to treat anxiety-related behaviors, the effects of Meth in combination with Bup on anxiety-like behavior are unclear. In this study, we examined the effects of these drugs on anxiety-like behavior with the elevated plus maze (EPM) and open field (OF) tests, which are widely used to assess anxiety-like behavior in small rodents. Forty male Wistar rats were divided into four groups: sham, Meth, Bup, and Bup+Meth. The groups were administered their assigned treatments for 7days. The time spent in the open arms, and number of total entries into the arms (total activity) in the EPM were recorded. In addition, locomotor activity and number of entrances into the center area in the OF were recorded. The 7-day administration of Meth or Bup increased open arm exploration in the EPM. In contrast, the combined administration of Bup and Meth had the opposite effects. In addition, Meth and Bup had no effects on total and locomotor activity. Furthermore, the rats in the Meth and Bup groups spent more time in the center of the OF, while the group given both Bup and Meth spent less time in the center of the OF. The administration of Meth and Bup alone was anxiolytic in rats, whereas the coadministration of Bup and Meth was anxiogenic.

Treadmill exercise alters ecstasy- induced long- term potentiation disruption in the hippocampus of male rats.

3, 4-methylenedioxymethamphetamine (MDMA) or ecstasy is a derivative of amphetamine that leads to long term potentiation (LTP) disruption in the hippocampal dentate gyrus (DG). Exercise has been accepted as a treatment for the improvement of neurodegenerative disease. Herein, the effects of exercise on the MDMA- induced neurotoxicity were assessed. Male Wistar rats received intraperitoneal injection of MDMA (10 mg/kg) and exercised for one month on a treadmill (Simultaneously or asynchronously with MDMA). LTP and expression of BDNF were assessed using electrophysiology and western blotting methods, respectively. MDMA attenuated the field excitatory post-synaptic potential (fEPSP) slope in comparison with the control group, whereas treadmill exercise increased this parameter when compared to MDMA group. Furthermore, BDNF expression significantly decreased in MDMA group and treadmill exercise could increase that. In conclusion, results of this study suggest that synchronous exercise is able to improve MDMA-induced LTP changes through increase of BDNF expression in the hippocampus of rats.

Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet- fed rats.

Obesity and consumption of a high fat diet (HFD) are known to increase the risk of Alzheimer's disease (AD). In the present study, we have examined the protective and therapeutic effects of thymol (main monoterpene phenol found in thyme essential oil) on a HFD-fed rat model of AD. Fourty adult male Wistar rats were randomly assigned to 5 groups:(n = 8 rats/group): group 1, control, consumed an ordinary diet, group 2 consumed a HFD for 8 weeks, then received phosphate-buffered saline (PBS) via intrahippocampal (IHP) injection, group 3 consumed HFD for 8 weeks, then received beta-amyloid (Aß)1-42 via IHP injections to induce AD, group 4 consumed HFD for 8 weeks, then received Aß1-42, and was treated by thymol (30 mg/kg in sunflower oil) daily for 4 weeks, and group 5 consumed HFD for 8 week, then received Aß1-42 after what sunflower oil was administered by oral gavage daily for 4 weeks. Biochemical tests showed an impaired lipid profile and higher glucose levels upon consumption of HFD, which was ameliorated by thymol treatment. In behavioral results, spatial memory in group 3 was significantly impaired, but groups treated with thymol showed better spatial memory compared to group 3 (p ≤ 0.01). In histological results, formation of Aß plaque in hippocampus of group 3 increased significantly compared to group 1 and group 2 (p ≤ 0.05), but group 4 showed decreased Aß plaques compared to group 3 (p ≤ 0.01). In conclusion, thymol decreased the effects of Aß on memory and could be considered as neuroprotective.

Neuroprotective effects of metformin against Aß-mediated inhibition of long-term potentiation in rats fed a high-fat diet.

Metformin (Met) is used to treat neurodegenerative disorders such as Alzheimer's disease (AD). Conversely, high-fat diets (HFD) have been shown to increase AD risk. In this study, we investigated the neuroprotective effects of Met on ß-amyloid (Aß)-induced impairments in hippocampal synaptic plasticity in AD model rats that were fed a HFD. In this study, 32 adult male Wistar rats were randomly assigned to four groups: group I (control group, regular diet); group II (HFD+vehicle); group III (HFD+Aß); or group IV (Met+HFD+Aß). Rats fed a HFD were injected with Aß to induce AD, allowed to recover, and treated with Met for 8 weeks. The rats were then anesthetized with intraperitoneal injections of urethane and placed in a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In vivo electrophysiological recordings were then performed to measure population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in the hippocampal dentate gyrus. Long-term potentiation (LTP) was induced by high-frequency stimulation of the perforant pathway. Blood samples were then collected to measure plasma levels of triglycerides, low-density lipoproteins, very low-density lipoprotein, and cholesterol. After induction of LTP, PS amplitude and EPSP slope were significantly decreased in Aß-injected rats fed a HFD compared to vehicle-injected animals or untreated animals that were fed a normal diet. Met treatment of Aß-injected rats significantly attenuated these decreases, suggesting that Met decreased the effects of Aß on LTP. These findings suggest that Met treatment is neuroprotective against the detrimental effects of Aß and HFDs on hippocampal synaptic plasticity.

The interactive role of CB(1) and GABA(B) receptors in hippocampal synaptic plasticity in rats.

Long-term potentiation (LTP) of synaptic transmission is a cellular process underlying learning and memory. Cannabinoids are known to be powerful modulators of this kind of synaptic plasticity. Changes in GABAergic inhibition have also been shown to affect synaptic plasticity in the hippocampus. GABA receptor type B (GABAB) and cannabinoid receptor type 1 (CB1) exhibit overlapping anatomical localization in some brain areas including the hippocampus. CB1 and GABAB are also localized to the same cells and share a common signaling pathway in some brain areas. In this study, we examined the hippocampal effects of co-administrating AM251 and CGP55845, which are CB1 and GABAB antagonists, respectively, on LTP induction in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS) of the perforant path. Our results showed that HFS coupled with administration of the CB1 antagonist increased both the population spike (PS) amplitude and field excitatory post-synaptic potential (fEPSP). Conversely, the GABAB antagonist decreased these parameters along with decreased LTP induction. We also demonstrated that the co-administration of CB1 and GABAB antagonists had different effects on the PS amplitude and fEPSP slope. It is likely that GABAB receptor antagonists modulate cannabinoid outputs that cause a decrease in synaptic plastisity, while in the simultaneous consumption of two antagonists, CB1 antagonists can alter the release of GABA which in turn results in enhancement of LTP induction. These findings suggest that there are functional interactions between the CB1 and GABAB receptor in the hippocampus.