Behavioral and molecular effects of intrahippocampal infusion of auraptene,resveratrol,and curcumin on H-89-induced deficits on spatial memory acquisition and retention in Morris water maze

Abstract

Our aim was to investigate the effects of resveratrol, auraptene, and curcumin on the spatial learning and spatial memory retention in the Morris water maze (MWM). The effects of 4-day bilateral intrahippocampal (i.h.) infusions of dimethyl sulfoxide (DMSO), H-89 as a protein kinase AII inhibitor, auraptene/H-89, resveratrol/H-89, and curcumin/H-89 were investigated on spatial memory acquisition in MWM. The rats were trained for 4 days; each day included one block of four trials. Post-training probe tests were performed on day 5 in acquisition test. For retention assessments, different animals were trained for 4 days and then infused (i.h.) with either DMSO, H-89, auraptene/H-89, resveratrol/H-89, or curcumin/H-89. The retention test was performed 48 h after the last training trial. The bilateral infusion of H-89 led to a significant impairment in spatial memory in acquisition and retention tests accompanied with a significant decrease in expressions of cAMP response-element binding (CREB) and pCREB proteins in hippocampus. Resveratrol and curcumin reversed the H-89-induced spatial memory acquisition and retention impairments with significant increases in both CREB and pCREB proteins expressions compared to H-89-treated animals. Auraptene showed significant effects in reversing H-89-induced impairments in spatial memory retention but not spatial memory acquisition.

Keywords

Resveratrol auraptene curcumin Morris water maze spatial memory hippocampus CREB pCREB

Introduction

In the industrialized world, the population is increasingly being older with deteriorating brain functions and responses to the intellectual stimuli. Oxidative stress and free radicals are involved in many diseases including cardiovascular, inflammatory, and cerebral diseases.^1
–3 Brain is especially vulnerable to oxidative stress leading to neurodegenerative diseases.^4,5

Phytochemicals found in herbal beverages and foods have crucial scavenging roles for oxidants and free radicals. A large body of literature has shown their protective effects against cancer, cardiovascular, and cerebral diseases.^5
–7 It is well characterized that a healthy diet enriched in such phytochemicals may delay the emergence of neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease.^8,9 The negative correlation between the frequency of consumption of natural products and the development of neurodegenerative diseases^10
–12 and cognition deficits⁸ has been well documented. Regular consumption of fruit, vegetables, and fish lowered cognition deficits in elderly people.⁸ Phytochemicals with potent antioxidant, free-radical scavenging, and neuroprotective properties are resveratrol, curcumin, and auraptene.^13
–15

Dorsal hippocampus, as a part of the limbic system, executes a critical role in spatial learning in rats and other mammals. This is warranted regarding poor performances in memory tasks such as Morris water maze (MWM) that were induced by hippocampal lesions or pharmacological interventions.^16
–18

A ubiquitous cellular kinase, cAMP-dependent protein kinase (PKA), that phosphorylates serine and threonine residues in response to cAMP elevation is an important signaling molecule participating in various cellular functions. PKA has an important role in the formation of different phases of memory and plays a critical role in the consolidation of short-term changes in neuronal activity into long-term memory.^19,20 H-89 (n-(2-aminoethyl)-5-isoquinoline-sulfonamide) is the most potent and selective PKA inhibitor which has been widely applied for the assessment of PKA function in the heart, osteoblasts, hepatocytes, smooth muscle cells, neuronal tissues, and epithelial cells.¹⁹ Previous studies showed that post-training bilateral intrahippocampal (i.h.) infusion of H-89 impaired spatial memory retention in MWM and decreased the density of choline acetyltransferase immunostaining in the dorsal hippocampus and the quantity of immunopositive neurons in the medial septal area.²¹

Resveratrol is a phytoalexin with potent antioxidant and neuroprotective effects available at high concentrations in peanuts and black grapes.²² Many lines of evidences have shown that resveratrol protects hippocampus from ischemia/reperfusion deleterious effects.^22
–24

Curry spice, also known as curcumin yellow constitute, has been used as a neuroprotective agent in a variety of neurodegenerative diseases including AD.^25
–27

On the other hand, auraptene (7-hydroxycoumarin) has also demonstrated wide-range of anti-inflammatory, neuroprotective, and antioxidant effects.

Considering the vast pharmacological properties of the mentioned natural and pharmaceutical compounds, we here aimed to evaluate the i.h. effects of H-89 on spatial memory acquisition and retention in MWM. As well, we explored potential protective effects of auraptene, resveratrol, and curcumin on H-89-induced spatial memory acquisition and retention impairments in male rats in MWM.

Materials and methods

Animals

Male Wistar rats (180–220 g) were purchased from the Faculty of Pharmacy, Zabol University of Medical Sciences. The animals were housed at 25 ± 2°C with a 12-h light/12-h dark cycle and free access to food and water. All animal procedures were done in accordance with the guidelines Ethical Committee for the care and use of laboratory animals of Zabol University of Medical Sciences (ethic code: ZBMU.1.REC.1394.147).

Drugs

H-89 (n-(2-aminoethyl)-5-isoquinoline-sulfonamide), auraptene, resveratrol, and curcumin were purchased from Sigma-Aldrich Chemical Co (St Louis, Missouri, USA). They were dissolved in dimethyl sulfoxide (DMSO; 0.2%) to obtain desirable concentrations (5 and 10 μM). Ketamine (100 mg/kg, intraperitoneal (i.p.)) and xylazine (25 mg/kg, i.p.) were used for induction of anesthesia for stereotaxic surgery. cAMP response-element binding protein (CREB), pCREB (serine 133), and anti-β-actin antibodies and secondary rabbit antibodies were purchased from Cell Signaling (Beverly, Massachusetts, USA). Coomassie (Bradford) Protein Assay Kit was purchased from Thermo scientific (Rockford, Illinois, USA).

Surgery, drug infusions, learning, and memory assessments

After induction of anesthesia by ketamine and xylazine, bilateral cannulation was performed based on Paxinos and Watson’s atlas of the rat brain in the CA1 region of the hippocampus using a stereotaxic instrument. Four-day bilateral i.h. infusions of DMSO (0.2%), H-89 (10 μM/side), auraptene (2.5, 5, 10 μM/side) + H-89 (10 μM/side), resveratrol (25, 50, 100 μM/side) + H-89 (10 μM/side), and curcumin (10, 25, 50 μM/side) + H-89 (10 μM/side) were administrated. The spatial memory acquisition in MWM task was investigated. Bilateral i.h. infusions of all the agents were carried out through guide cannula in a volume of 1 μl per side. Rats were trained for 4 days; each day included one block of four trials and all infusions were done 30 min before training in each day. Post-training probe tests were performed on day 5 in acquisition test. In probe trial tests, the hidden platform was removed and animals were allowed to swim freely for 90 s.

For retention assessments, the animals were trained for 4 days and were infused (i.h.) with DMSO (0.2%), H-89 (5 μM/side), auraptene (2.5 μM/side) + H-89 (5 μM/side), resveratrol (100 μM/side) + H-89 (5 μM/side), and curcumin (25μM/side) + H-89 (5 μM/side) after the last training trial. The retention test was performed on day 6. In the groups with combined treatments, the infusions were administrated with 15-min interval between each microinjection.

Spatial memory was assessed by EthoVision video tracking system (Noldus Information Technology, Wageningen, The Netherlands) through measuring escape latency, traveled distance, swimming speed, and time spent in target quadrant (the quadrant included hidden platform during training trials).

Western blot analysis

For the assessment of CREB and pCREB proteins expressions, 200 mg of hippocampi of rats was isolated and stored at −80°C. The tissues were homogenized using a mechanical homogenizer on ice. Then, supernatants were collected, protein contents were measured, and the samples were put in warm bath for denaturation of proteins. After that, the samples were electrophoresed in acrylamide gel, transferred to polyvinylidene fluoride membrane, and blocked with skim milk. Finally, the samples were treated with the primary and secondary antibodies. Next, chemiluminescent was used using Syngen Chemidoc. Eventually, blot analyses were done using GeneTools software (SynGene, Cambridge, UK).

Statistical analysis

The data obtained were analyzed using GraphPad Prism version 5.0. One-way analysis of variance followed by Newman–Keuls post hoc test was used to compare the behavioral and molecular data. The results were considered statistically significant at p < 0.05.

Results

Effects of auraptene, resveratrol, and curcumin on H-89-induced spatial memory acquisition impairment in MWM

As shown in Figure 1(a) to (f), H-89 (10 µM/side)-treated animals showed significant increase in both traveled distance (**p < 0.01) and escape latency (**p < 0.01) parameters compared to DMSO-treated animals (control group). Neither of administered doses of auraptene did not alter the PKA AII inhibitor-induced spatial memory acquisition deficits (Figure 1(a) and (b)). In interactive assessments, a significant decrease in traveled distance and escape latency parameters was observed for resveratrol/H-89 (Figure 1(c) and (d)) and curcumin/H-89 (Figure 1(e) and (f))-treated animals compared to H-89-treated group. No significant differences were found in swimming speed between these treated animals (p > 0.05) in comparison with their related controls (data not shown).

Figure 1.

Average of traveled distance (a, c, and e) and escape latency (b, d, and f) parameters in H-89, auraptene/H-89 (a and b), resveratrol/H-89 (c and d), and curcumin/H-89 (e and f)-treated animals in the MWM task (spatial memory acquisition evaluations). **p < 0.01 shows a considerable difference from control group. ^#p < 0.05, ^##p < 0.01, ^###p < 0.001, and ^####p < 0.0001 significantly different from H-89-treated animals. Values represent means ± SEM of eight animals in each group. MWM: Morris water maze; SEM: standard error of the mean.

Evaluation of probe test in H-89, auraptene/H-89, resveratrol/H-89, and curcumin/H-89-treated animals in MWM

I.h. infusion of H-89 (10 µM/side) significantly decreased the time spent in target quadrant (the quadrant which was included hidden platform) compared to control animals (Figure 2). There were no significant differences between auraptene/H-89 and H-89-treated animals (Figure 2(a)). The time spent in target quadrant was increased significantly in animals treated with combination of resveratrol (50 and 100 µM/side)/H-89 (Figure 2(b)) or curcumin (25 µM/side)/H-89 (Figure 2(c)) compared to H-89-treated animals.

Figure 2.

Evaluation of time spent in the target quadrant in auraptene/H-89 (a), resveratrol/H-89 (b), and curcumin/H-89 (c)-treated animals in probe test. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 significantly different from control group. ^##p < 0.01 and ^###p < 0.001 significantly different from H-89-treated animals. Values represent means ± SEM of eight animals in each group. SEM: standard error of the mean.

Effects of auraptene (2.5 µM/side), resveratrol (100 µM/side), and curcumin (25 µM/side) on H-89-induced spatial memory retention impairment in MWM

As shown in Figure 3(a) to (f), H-89 (5 µM/side)-treated animals showed significant increase in both traveled distance (**p < 0.01) and escape latency (**p < 0.01) parameters compared to DMSO-treated animals (control group). In interactive assessments, significant decreases were observed in traveled distance and escape latency parameters in auraptene (2.5 µM/side)/H-89 (Figure 3(a) and (b)), resveratrol (100 µM/side)/H-89 (Figure 3(c) and (d)), and curcumin (25 µM/side)/H-89 (Figure 3(e) and (f))-treated animals compared to H-89-treated group. No significant differences were found in swimming speed between these treated animals (p > 0.05) in comparison with their related controls (data was not shown).

Figure 3.

Average of traveled distance (a, c, and e) and escape latency (b, d, and f) parameters in H-89, auraptene/H-89 (a and b), resveratrol/H-89 (c and d), and curcumin/H-89 (e and f)-treated animals in the MWM task (spatial memory retention evaluations). *p < 0.05 and **p < 0.01 show a considerable difference from control group. ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 significantly different from H-89-treated animals. Values represent means ± SEM of eight animals in each group. MWM: Morris water maze; SEM: standard error of the mean.

The effect of i.h. infusion of H-89, auraptene/H-89, curcumin/H-89, and resveratrol/H-89 on the expression of CREB and pCREB proteins in the hippocampus of male rats in acquisition phase of spatial memory

I.h. infusion of H-89 (10 µM/side) significantly decreased the expression of CREB and pCREB proteins in comparison with control animals (***p < 0.001). Curcumin (25 µM/side) and resveratrol (100 µM/side) significantly reversed the H-89-induced CREB expression (^##p < 0.01) in comparison with H-89-treated animals (Figure 4). Auraptene did not cause any significant alterations on CREB and pCREB levels (Figures 4 and 5).

Figure 4.

Assessment of CREB protein expression in hippocampus of H-89, auraptene/H-89, curcumin/H-89, and resveratrol/H-89-treated animals (acquisition phase of spatial memory). ***p < 0.001 significantly different from control group. ^##p < 0.01 significantly different from H-89-treated animals. Values represent means ± SEM of six animals in each group. CREB: cAMP response-element binding; SEM: standard error of the mean.

Figure 5.

Assessment of pCREB protein expression in hippocampus of H-89, auraptene/H-89, curcumin/H-89, and resveratrol/H-89-treated animals (acquisition phase of spatial memory). ***p < 0.001 significantly different from control group. Values represent means ± SEM of six animals in each group. SEM: standard error of the mean.

The effect of i.h. infusion of H-89, auraptene/H-89, curcumin/H-89, and resveratrol/H-89 on the expression of CREB and pCREB proteins in the hippocampus of male rats in retention phase of spatial memory

Post-training i.h. infusion of H-89 (5 µM/side) significantly decreased the expressions of CREB and pCREB proteins in comparison with control animals (***p < 0.001). Auraptene (2.5 µM/side), curcumin (25 µM/side), and resveratrol (100 µM/side) significantly (^#p < 0.05, ^##p < 0.01, and ^###p < 0.001, respectively) reversed (but not to the control level) the altered expression of CREB in H-89-treated animals (Figure 6).

Figure 6.

Assessment of CREB protein expression in hippocampus of H-89, auraptene/H-89, curcumin/H-89, and resveratrol/H-89-treated animals (retention phase of spatial memory). ***p < 0.001 significantly different from control group. ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 significantly different from H-89-treated animals. Values represent mean ± SEM of six animals in each group. CREB: cAMP response-element binding; SEM: standard error of the mean.

Auraptene (2.5 µM/side), curcumin (25 µM/side), and resveratrol (100 µM/side) significantly (^###p < 0.001) reversed (but not to the control level) the H-89-induced pCREB expression decrease in comparison with H-89-treated animals (Figure 7).

Figure 7.

Assessment of pCREB protein expression in hippocampus of H-89, auraptene/H-89, curcumin/H-89, and resveratrol/H-89-treated animals (retention phase of spatial memory). ***p < 0.001 significantly different from control group. ^###p < 0.001 significantly different from H-89-treated animals. Values represent means ± SEM of six animals in each group. SEM: standard error of the mean.

Discussion

Despite many therapeutic advances in memory deficit diseases, neurodegenerative diseases are still among the most dreadful conditions worldwide.^28,29 Natural products, especially resveratrol, curcumin, and auraptene, which are found in routine human diets, have been under focus for their neuroprotective effects in recent years.^25,30,31

On the other hand, H-89 is an inhibitor of PKA that is widely used for elucidating the role of PKA signal transduction in cell biological activities.¹⁹ In this study, H-89 was used to evaluate the potential beneficial effects of resveratrol, curcumin, and auraptene on improvement of spatial memory acquisition and retention. As the signal transduction pathway of PKA/CREB/pCREB is of crucial importance in spatial memory function, the expression of CREB and pCREB was also assessed.

In fact, H-89 inhibits PKA signaling through the inhibition of CREB and pCREB proteins expression.¹⁹ CREB and pCREB proteins are involved in the synaptogenesis and neurogenesis in the brain. Many studies have confirmed that increased levels of these proteins inhibited memory deficits and neurodegenerative diseases.^32,33

Our results demonstrated that resveratrol and curcumin reversed H-89-induced spatial memory acquisition and retention impairments with a significant increase in both CREB and pCREB proteins expression. Besides, auraptene also significantly improved the spatial memory retention.

Resveratrol has shown neuroprotective effects in previous studies. Actually, resveratrol can prohibit age-related memory deficit and AD by reversing beta amyloid peptides-induced cytotoxicity.^33

–36 It has been shown that resveratrol acts as a PDE4 inhibitor that can increase PKA levels and also activates CREB and its active form, pCREB.³³ Our results also indicated that resveratrol can reverse the impairments in spatial memory acquisition and retention by activation of cAMP/CREB signaling pathway. Furthermore, previous studies have also noted that resveratrol may promote its neuroprotective effects by activating the Silent Information Regulator T1 gene contributing to impaired learning and memory through microRNA-CREB-BDNF pathway.^31,37 Resveratrol can also increase BDNF, the downstream target of CREB, and improve memory function in animal models.^37,38 Furthermore, many lines of evidences showed that resveratrol could protect hippocampus from ischemia/reperfusion deleterious effects.^22
–24

Curcumin exhibited activity against AD.²⁷ It has been reported that in the traumatic brain injury model induced by high-fat diet, curcumin induced synaptic plasticity and increased cognitive function.²⁶ These effects were shown to be correlated to the levels of CREB and BDNF proteins.²⁶ In another study, it was shown that curcumin reversed memory deficits by increasing BDNF and pCREB/CREB protein levels in a chronic stress animal model.³⁰ In our study, curcumin reduced spatial memory acquisition and retention impairments by accompanying with a significant increment in CREB and/or pCREB protein levels.

In our previous experiment, we showed that auraptene consolidated memory function following to scopolamine-induced memory retention deficit in animal models. Here, we here evaluated auraptene impacts on H-89-induced spatial memory acquisition and retention deficit. Another study showed that auraptene could reverse spatial memory deficit in AD.³⁹ This was in accordance with our study that showed auraptene can improve H-89-induced spatial memory retention deficits in MWM via increasing of CREB and pCREB protein expressions.

Conclusions

Auraptene, resveratrol, and curcumin showed significant effects in reversing H-89-induced impairments in spatial memory acquisition and retention likely through regulating CREB and/or pCREB pathways.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

A Bazi

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