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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2026 The   Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access Full Text Article  Research Article

ResArgin^TM, a conjugate of resveratrol and arginine, prevents memory impairment and oxidative stress in the Alzheimer’s disease rat model intoxicated with aluminum chloride

Injoh Nicoline Agwe ¹, Boris Gabin Kingue Azantsa ¹*, Nikanor Rudig Tadah Djikem ², Dupon Akamba Ambamba ¹, Julius Oben ^1,3

¹ Laboratory of Nutrition and Nutritional Biochemistry, Department of Biochemistry, Faculty of Science, University of Yaounde 1, Cameroon P.O. Box: 812 Yaounde, Cameroon.

² Laboratory of Animal Biology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde 1, Cameroon. P.O. Box: 812 Yaoundé, Cameroon.

³ Research and Development Department, Cameroon Nutrition and Dietetic Research Centre, J&A Oben Foundation, Yaounde P.O. Box 8348

 

 

1. INTRODUCTION

Alzheimer's disease (AD) is the most common form of neurodegeneration, manifesting as memory loss, cognitive decline, brain shrinkage, creation of extracellular senile plaques, and intracellular neurofibrillary tangles¹. Oxidative stress has been shown to play a crucial role not only in the early stages of Alzheimer's disease prior to cytopathology, but also in the induction and activation of various cellular signaling pathways that contribute to the formation of lesions caused by toxic substances, thereby promoting the development of AD². In aluminum chloride-induced rat models of Alzheimer's disease, oxidative stress has been shown to accelerate the neuropathology of Alzheimer's disease by promoting increased phosphorylation of tau, an accumulation of insoluble beta-amyloid peptide (Aβ), its deposition, and dysfunction of cholinergic enzymes (AchE and BuchE)³. The challenge of current research is to find compounds capable of preventing and treating AD, especially as drugs are scarce against it⁴. In this light, antioxidant compounds are increasingly being explored for their anti-Alzheimer's potential. This explains why up to three compounds (hydralazine hydrochloride, omega-3, and icosapentethyl) are registered in the Alzheimer's drug development pipeline for 2023 phase 3 trials targeting oxidative stress⁵. Additionally, the Keap1-Nrf2 pathway has been established as a therapeutic target for AD^6,7. Several studies have revealed the neuroprotective effect of resveratrol thanks to its antioxidant effects⁸. However, its physicochemical and pharmacokinetic properties have shown their limitations⁹. In addition, its multiple biological effects (anti-obesity, anti-cancer, anti-diabetes, anti-ageing) show that it deserves to be promoted as a hit compound⁸. Recently, data reported significant improvements in microvascular function when 90 mg of resveratrol was consumed in the form of ResArgin™ (a conjugate of resveratrol and arginine), thus showing that ResArgin™ is a lead that can have more biological effects than its hit (resveratrol)¹⁰. This study presents the antioxidant effects of ResArgin™ and its protective effects against memory loss in a rat model of AD induced by Aluminium chloride. 

2. MATERIALS AND METHOD

2.1. Drugs and chemicals

Drugs: ResArgin^TM (a conjugate of resveratrol and the amino acid arginine) was obtained from Gateway Health Alliance Fairfield, California (Figure 1). Donepezil was purchased from the pharmacy (Yaoundé, Cameroon). Chemicals: All the chemicals used were of analytical grade and were purchased from Sigma Aldrich St Louis Mo, USA.

 

                    

Figure 1: Chemical structure of ResArgin^TM

 

2.2. Experimental animals

Thirty-six adult female Wistar rats weighing 230-250g were obtained from the animal house of the Laboratory of Nutrition and Nutritional Biochemistry of the University of Yaoundé 1, Cameroon. They were housed in clean cages and maintained under standard conditions (room temperature with dark/light cycle 12/12 h). The rats were fed with a standard diet and had free access to potable water. They were acclimatized for seven days. 

2.2.1. Ethical approval  

Animals were treated following the guidelines of the ethical committee of the University of Yaoundé 1 and the Guide for the Care and Use of Laboratory Animals (8th edition).

2.2.2. Animal Experimentation 

Testing the antioxidant potential and neuroprotective effect of ResArgin^TM against aluminum chloride-induced neurotoxicity in rats

2.2.3. Treatments 

The animals were randomly divided into six groups- a normal control (NC) (receiving distilled water only), a positive control (PC) (aluminum chloride at 50mg/kg bodyweight and distilled water), test group1 (50mg/kg bw AlCl₃ and ResArgin ^TM at 300mg/kgbw), test group 2 (50mg/kgbw AlCl₃ and ResArgin^TM at 500mg/kgbw), Reference 1 (50mg/kg bw AlCl₃ and Donepezil at 1 mg/ kgbw) and Reference 2 (50mg/kg bw AlCl₃ and Vitamin E at 100mg/kg bw). After one hour, ResArgin ^TM and reference drugs were administered to their corresponding groups, and the experimental period lasted for 42 days¹¹.

Table 1: Treatment summary 

Groups	Treatments
NC	distilled water
PC	50mg/kg bw AlCl3 + distilled water
Test 1 RSA300	50mg/kg bw AlCl3 + 300mg/kg:bw ResArginTM
Test 2 RSA 500	50mg/kg bw AlCl3 + 500mg/kg:bw ResArginTM
Reference 1 DNPZ (AD)	50mg/kg bw AlCl3 + 1 mg /kg bw Donepezil
Reference 2 Vit E (Antioxidant)	50mg/kg bw AlCl3 + 100mg /kgbw Vitamin E

RSA: resargin^TM; DNPZ: Donepezil; Vit E: vitamin E

 

2.2.4. Cognitive test                                                            

2.2.4.1. Elevated plus-maze (EPM) test

This study was carried out according to the protocol described by Walf and Frye¹². The elevated plus-maze (EPM) is the most effective apparatus for the screening of anti-anxiety drugs. The elevated plus maze produced a novel environment that helped induce anxiety in animals because of the open nature of the arms and the elevation from the floor¹³. Rats present in the EPM prefer exploring the enclosed arms. Anxiety is marked by immobility and defecation. The parameters noted were time spent in open/closed arms, number of entries in the open/closed arms, number of rearing, weight of fecal body, and number of grooming. The percentages of time spent and the number of entries in each type of arm were calculated for each animal. After the test, the rectal temperature of each animal was measured using a medical thermometer.

2.2.4.2. Morris Water Maze test 

The Morris water maze (MWM) test provides an accurate and reproducible measure of spatial memory and is a highly sensitive tool for assessing hippocampal damage¹⁴. In the present study, the MWM test was performed in a black circular tank (diameter 120 cm × height 50 cm), half-filled with water in a lighted room. An 8-cm-diameter black drainage platform (colored to match the apparatus to make it invisible) was placed in a fixed position (south quadrant of the apparatus), submerged 1.0 cm below the water surface. The test included a 5-day acquisition and retention phase on day 6. Acquisition phase: Three trials were performed daily, with a 15-minute break between trials. At the end of each trial, the animals were properly cleaned and returned to their home cages. The principle of the MWM was that when the rats escaped from the water by climbing onto the platform, they learned the spatial location of the platform from any starting position in the pool. Retention phase: During this phase, to assess spatial memorization, the platform was removed, and each rat was released into the water in one of the fixed targets facing the target quadrant and had 60 seconds to swim and find the platform. A video recording system was used, and a camera was placed above the pool and connected to a computer. The videos were analyzed using Any-maze 7.3 software. The latency time to reach the exact position of the platform, the time spent in the target quadrant, and the number of entries in the target quadrant of the platform were recorded.

2.3. Animal sacrifice

2.3.1. Brain and blood tissue collection 

At the end of the experiment period, animals were sacrificed by cervical decapitation after 12 hours of fasting. Blood samples were collected from the trunk in tubes containing EDTA and centrifuged at 1500 g at 4 °C for 15 min to obtain plasma.

2.3.2. Histopathological examination

One of the cerebral hemispheres of each rat was fixed in 10% formaldehyde, embedded in paraffin, cut (5 µm sections in the coronal plane), and processed for hematoxylin-eosin staining using standard procedures.

 2.3.3. Preparation homogenate brain

 The brains were rapidly removed, weighed, and thoroughly washed with isotonic saline. Brains were homogenized in 10 volumes of ice-cold (4 °C) medium containing 50 mM Tris (hydroxymethyl) aminomethane-HCl (Tris-HCl) buffer, pH 7.4, with 300 mM sucrose. Then, the homogenate was centrifuged (1000 g for 10 min). The resulting supernatant was immediately stored at -20 °C and used for biochemical analyses.

2.3.4. Oxidative stress markers  

a) Malondialdehyde

The protocol was adopted with slight modifications as previously described¹⁵. Carbonyl compounds such as malondialdehyde react with thiobarbituric acid (TBA) to give pink chromophores absorbing at 530 nm. One hundred micro-liters of homogenate or 0.9%NaCl (blank), 250μL of trichloroacetic acid (TCA) 20% and 400μL of TBA 0.67% were added to the glass screw-top tubes (blank and test) and sealed. The mixture was heated in a water bath at 100⁰C for 15 min and then cooled in a cold-water bath for 30 min. The tubes were left open to allow the gases formed during the reaction to escape. They were then centrifuged at 1500 rpm for 5 min, and the absorbance of the supernatant was read at 532 nm against the blank. The concentration of MDA was expressed in µM/g of brain.

b) Reduced Glutathione 

The method was based on the measurement of thiol groups by monitoring the concentration of yellow-colored TNB (5-thio-2-nitrobenzoic acid), formed by reduction of DTNB (5,5-dithiobis (2-nitrobenzoic acid). One hundred (100) μL of homogenate and 900μL of Ellman’s reagent were respectively introduced into blank and test tubes. After homogenization, the mixture was incubated at room temperature for 30 minutes. Optical densities were read at 420 nm against the blank containing 900μL of reagent solution and 100 μL of NaCl (0.9%), incubated under the same conditions. The concentration of reduced GSH in the brain tissues was expressed as µM/g of the brain¹⁶.

c) Catalase Activity (EC 1.11.1.6)

Catalase present in the homogenate reduces hydrogen peroxide (H₂O₂) to water (H₂O) and oxygen (O₂). H₂O₂, not reduced by catalase, binds to potassium dichromate to form a blue-green precipitate of unstable perchloric acid. This is then decomposed by heat to form a green complex that absorbs at a wavelength of 570 nm. Catalase activity was proportional to optical density and was determined using a calibration curve. The activity was expressed as mmol H₂0₂ consumed/min/mg protein/g brain¹⁷.

d) Superoxide dismutase activity (EC 1.15.1.1) 

The method described by Misra and Fridovich¹⁸ was adopted. The method was based on the fact that SOD present in a sample inhibits the oxidation of adrenaline to adrenochrome. An aliquot of 0.2 mL of brain homogenate was introduced into 2.5 mL carbonate buffer (pH 10.2) to equilibrate the spectrophotometer. The reaction was then started by adding 0.3 mL of freshly prepared adrenaline to the mixture. After homogenization by inversion, the final mixture was read at 480 nm every 30 s for 150 s to follow the increase in absorbance. SOD activity was reported as units per g of brain.

e) Glutathione peroxidase (GPx) (EC 1.11.1.9) activity assay 

GPx catalyses the reaction of hydroperoxides with reduced glutathione to form glutathione disulfide (GSSG) and the reduction product of hydroperoxide. The GPx activity of the sample was monitored at the rate of the decrease in reduced glutathione using H₂O₂ as a substrate according to the method of Flohe and Gunzler¹⁹. To 50 µL of the sample, 100 µL of reduced glutathione (0.1 mM) and 200 µL of H₂O₂ (0.1 mM) were added. The samples were then pre-incubated at 25 °C in a water bath for 5 min. One millimeter of trichloroacetic acid (20%) was added to the samples. The tubes were further cooled on ice and centrifuged at 1000 g for 10 min. To 400 µL of supernatant fraction, 2.2 mL of phosphate buffer (50 mM; pH 7.0) and 320 µL of Ellman’s reagent (DTNB: 5,5-dithiobis-2-nitrobenzoic acid) were added. The absorbance was read at 412 nm after 5 min of reaction. One enzyme unit of GPx activity was defined as 1 µmol of glutathione oxidized per minute at 25 °C.

2.6. Statistical analysis

GraphPad Prism 10.2.2 software was used for statistical analysis. The normality test was confirmed by the Shapiro-Wilk test, and a one-way analysis of variance (ANOVA) with Tukey’s test was performed for comparison between groups. Results are expressed as mean value ± SD (n = 6). P < 0.05 was considered significant. 

3. Results

3.1. ResArgin^TM preserves learning patterns and protects spatial memory in rats given Aluminium Chloride (Morris Water Maze Test)

3.1.1. ResArgin^TM preserves learning patterns 

Figures 2 and 3 below show the progression in the escape latency for each trial at the second and sixth weeks, respectively. Figure 2 shows no difference in the average latency between all groups during week 2 in the Morris Water Maze test. During the sixth week (figure 3) of the Morris Water Maze, the average latency time in the positive control group increased compared to the normal control group. ResArgin^TM 500 restored memory function, as evidenced by a reduced average latency time compared to the positive control group.

  

Figure 2: Action of ResArgin^TM on the escape latency time into the target quadrant, week 2

Figure 3: Action of ResArgin^TM on escape latency into the target quadrant, week 6

3.1.2. ResArgin^TM protects spatial memory 

Table 2 shows the latency to reach the target quadrant, respectively, during the second and sixth weeks of the experiment (day-6).

 

 

Table 2: the latency time to reach the target quadrant, respectively, during the second and sixth weeks of the experiment (day-6)

Treatment groups	latency time into the target Second week of the experiment (s)	latency time into the target  Sixth week of the experiment (s)
Normal control	6.6 ± 0.78a	2.6 ± 0.23a
Positive control	4.7 ±1.1a	5.4±0.67b
RSA 300	7.2 ± 1.3a	4.2 ± 1.3b
RSA 500	5 ± 1.01a	2.3± 0.4a
DONEPEZIL	4.7 ± 0.92a	1.9 ± 0.3a

The numbers assigned to different letters (a,b) are significantly different (P<0.05); RSA: resargin^TM    

 

 

No significant difference was observed among all groups of the experiment with regard to the latency time to reach the target quadrant during the test day (day 6) of the second week. A significant difference (P < 0.05) in the latency time to reach the target quadrant was noted between NC and PC on test day (day 6), the sixth week of experimentation. Administration of ResArgin^TM reduced this latency time. This reduction (P<0.05) was more pronounced at the dose of 500mg/kg b.w. 

3.2. Anxiolytic action of ResArgin^TM 

Figure 4 shows the time spent on the open arm, and Figure 5 shows the time spent on the closed arm during the second and sixth weeks of the experiment.

 

   Figure 4: Time spent on the open arm

RSA: resargin^TM; DNPZ: Donepezil; NC: Normal control; PC: Positive control

   Figure 5: Time spent on closed arm

RSA: Resargin^TM; DNPZ: Donepezil; NC: Normal control; PC: Positive control

 

 

 

The results showed a significant decrease (P<0.01) in the time spent in the open arms of the PC group compared to the NC group. However, after administration of RSA300 and RSA500, a non-significant increase was obtained in these groups compared to the PC groups. On the other hand, the analysis of the time spent in the closed arms showed no significant difference between the different groups.

 

.

3.3. Protective action of ResArgin^TM on the hippocampal microarchitecture 

Figure 6 shows the hippocampal microarchitecture (CA1,3 and DG)

Figure 6: Protective action of ResArgin^TM on hippocampal microarchitecture

 

 

In the normal control group, brain histology showed normal architecture of the different areas of the hippocampus (CA1, 3, and DG), while in the positive control group treated with aluminum, rat brain histology showed the presence of apoptosis, suggesting neurotoxicity induced by aluminum chloride. In the groups treated with ResArgin^TM, brain histology showed normal histology, demonstrating protection against aluminum chloride neurotoxicity compared to the positive control group. 

 

 

 

3.4. ResArgin^TM boosts brain antioxidant status

Table 3 shows the Effect of ResArgin^TM on cerebral antioxidant status in female rats.

 

Table 3: ResArgin^TM boosts brain antioxidant status

Treatment groups	SOD (U/mg protein/g of brain)	Catalase (mmol H202 consumed/ min/mg protein/g brain)	Glutathione (U/mg protein of brain)	MDA (µM/g of brain)
Normal control	1.48 ± 0.06a	4.2±0.1a	0.41 ± 0.02a	5.19 ± 0.84a
Positive control	1.08±0.08b	1.6±0.1b	0.18 ± 0.01b	9.23 ± 1.31b
RSA 300	1.249 ± 0.03a	3.6± 0.2b	0.30 ±0.01a	2.75 ±0.4a
RSA 500	1.36± 0.04a	4.40± 0.42a	0.31 ± 0.01a	4.59±0.42ab
Vitamin E 100	1.74 ± 0.02	2.35± 0.12	0.17±0.03	11.36 ±0.84

RSA: ResArgin^TM. The values are expressed as mean plus or minus standard error on the mean. Values with different values in the same column are significantly different.

 

In rat brain homogenate, statistical analysis shows a significant decrease in catalase, SOD, and glutathione peroxidase (GPx) activity in the positive control group compared to the normal control group.   There was a significant difference in rat brain catalase, SOD, and GPx in the ResArgin^TM 500-treated group compared to the positive control group, as shown in Table 3. ResArgin^TM significantly increased the levels of catalase, SOD, and GPx. 

Statistical analysis shows a significant (p<0.05) increase in the level of MDA between the positive control group and the normal control group, and a significant decrease in MDA level with the ResArgin^TM treated group compared to the positive control group. 

4. DISCUSSION

The search for effective treatments against AD remains a significant challenge today¹. Antioxidant compounds represent a rapidly growing therapeutic option for this disease^20,21. The present study was carried out to evaluate the preventive effect of ResArgin^TM on oxidative stress and behavioral changes in aluminum-induced neurodegeneration in rats as a model of AD. Once in the brain, aluminum starts to compete with and replace calcium, magnesium, zinc, and phosphorus in a variety of enzymes and proteins. As a result, it sets in motion a series of biochemical cascades involved in abnormal processes, which culminate, optionally, together with pathological and clinical symptoms known as Alzheimer's disease. Research shows that aluminum chloride exposure in humans and animals results in behavioral changes and intellectual impairment³.

The elevated plus maze test and the Morris water maze (MWM) tests were used to evaluate learning and memory¹⁴. In the MWM test, the learning profile in the PC was different from that of the NC in the sixth week of the test, which reflects an alteration of the memorization process by aluminum chloride. However, the treatment maintains the NC's learning profiles. Moreover, the PC group showed a significant (p<0.05) increase in escape latency compared to the normal control. This indicates an impairment in memory. Treatment with ResArgin^TM at different doses significantly decreased the escape latency in the sixth week, indicating memory retention (Figures 2 and 3). The EPM result shows a significant (p<0.01) reduction in the time spent in the open arm in the PC compared to the NC. However, this time increased in the treated groups. This result shows that ResArgin^TM may reduce anxiety levels in rats.  The hippocampus was selected for histological cuts because it plays a more specific role in memory formation and learning²². Treatment with aluminum chloride led to histological changes in the positive control group compared to the normal control group. ResArgin^TM 500-treated groups showed no hemorrhage or apoptosis in rat brains, indicating a neuroprotective effect (Figure 6). 

The cognitive decline that occurs from neurodegeneration is mainly caused by oxidative stress in the brain²³. Long-term exposure to aluminum chloride in female rats causes oxidative stress and changes in brain antioxidant enzymes²⁴. This study demonstrates that chronic aluminum exposure induces cognitive impairment and alters brain markers in female rats, suggesting a model for studying AD pathology. However, limitations exist; first, the exclusive use of female rats limits generalizability to male rats. Future studies should include both species. Secondly, the exclusive use of aluminum chloride for the induction of AD may not fully replicate the complex pathology of AD. Results should be interpreted cautiously and considered alongside other findings from other AD models. Aluminum induces neurotoxicity and, consequently, neurodegeneration. The results of the present study showed a significant decrease in catalase and SOD activities, with an increase in lipid peroxidation shown by elevated malondialdehyde levels in the positive control group compared to the negative control group. This indicated that a state of oxidative stress was induced, leading to the formation of free radicals in the brains of rats²⁴. Brain tissue is more susceptible to oxidative stress due to its greater oxygen consumption rate, high content of peroxidizable fatty acids, less regenerative capability, and low amounts of antioxidants. 

Treatment with ResArgin^TM 500 significantly elevated the levels of defensive antioxidant enzymes and decreased lipid peroxidation (Table 3). This indicates a restoration in oxidative stress balance in rat brains. SOD is a vital antioxidant that detoxifies reactive oxygen species and acts as a cofactor for antioxidants like catalase and glutathione peroxidase²⁵. This ability to restore the antioxidant system could be due to the presence of the amino acid arginine in addition to the hydroxyl groups found in ResArgin^TM. It has two amino groups in its structure; these are all electron-donating groups, which would scavenge the free radicals produced by donating their electrons^26,27. 

The efficacy of ResArginTM to prevent oxidative stress and memory loss could be explained by the enzymatic release of resveratrol and arginine from ResArgin^TM increasing plasma arginine level and consequently its bioavailability, usually limited to less than 24 hours²⁸. The increased bioavailability of arginine certainly sustains and prolongs its neuroprotective effects, probably via slow digestion/absorption processes. The longer/relatively permanent supply of arginine via digestion/absorption of ResArginTM may decrease acute inflammatory reaction²⁹, contribute to the production of neuropeptide vasopressin, reducing neuronal death and improving functional recovery^30,31.

5. CONCLUSION 

ResArgin^TM prevents memory loss, memory disorders, altered hippocampus areas, and oxidative stress induced by aluminum chloride in rats. 

Competing Interests: The authors have declared no competing interests.

Acknowledgements: We would like to thank the Animal Physiology Research Unit, the Laboratory of Nutrition and Nutritional Biochemistry of the University of Yaoundé 1 and the J&A Oben Foundation for providing all the necessary lab facilities.

Funding: The authors declare that no funds, grants, or other support were received for this work. 

Author Contributions: OJ and AKGB conceived, designed, and supervised the study. ANI and DTRN conducted cognitive experiments. AN, AABD and AKGB performed biochemical analyses, analyzed results, and drafted the manuscript. The final version of the manuscript was read and approved by all the authors.

REFERENCES

1. Chen X, Zhang M, Ahmed M, Surapaneni KM, Veeraraghavan VP, Arulselvan P, Neuroprotective effects of ononin against the aluminium chloride-induced Alzheimer’s disease in rats, Saudi Journal of Biological Sciences, 2021; 28:4232-4239 https://doi.org/10.1016/j.sjbs.2021.06.031 PMid:34354404 PMCid:PMC8325004

2. Dhapola R, Beura SK, Sharma P, Singh SK, HariKrishnaReddy D, Oxidative stress in Alzheimer’s disease: current knowledge of signaling pathways and therapeutics, Molecular Biology Reports, 2024; 51:48 https://doi.org/10.1007/s11033-023-09021-z PMid:38165499

3. Ojetunde AO, The Neuroprotective and Therapeutic Effects of Medicinal Plants and Natural Products against Aluminium Chloride-Induced Alzheimer’s Disease: Recent Update, Biology, Medicine, and Natural Product Chemistry, 2024; 13:7-33 https://doi.org/10.14421/biomedich.2024.131.7-33

4. Yu TW, Lane HY, Lin CH, Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review, International Journal of Molecular Sciences, 2021; 22:8208 https://doi.org/10.3390/ijms22158208 PMid:34360973 PMCid:PMC8348485

5. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F, Alzheimer’s disease drug development pipeline: 2023, Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 2023; 9: e12385 https://doi.org/10.1002/trc2.12385 PMid:37251912 PMCid:PMC10210334

6. Baird L, Yamamoto M, The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway, Molecular and Cellular Biology, 2020; 40: e00099-20 https://doi.org/10.1128/MCB.00099-20 PMid:32284348 PMCid:PMC7296212

7. Sun Y, Xu L, Zheng D, Wang J, Liu G, Mo Z, Liu C, Zhang W, Yu J, Xing C, He L, Zhuang C, A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer’s disease, Redox Biology, 2023; 64:102793 https://doi.org/10.1016/j.redox.2023.102793 PMid:37385075 PMCid:PMC10331597

8. Meng X, Zhou J, Zhao CN, Gan RY, Li HB, Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review, Foods, 2020; 9:340 https://doi.org/10.3390/foods9030340 PMid:32183376 PMCid:PMC7143620

9. Robertson I, Wai Hau T, Sami F, Sajid Ali M, Badgujar V, Murtuja S, Saquib Hasnain M, Khan A, Majeed S, Tahir Ansari M, The science of resveratrol, formulation, pharmacokinetic barriers and its chemotherapeutic potential, International Journal of Pharmaceutics, 2022; 618:121605 https://doi.org/10.1016/j.ijpharm.2022.121605 PMid:35227804

10.  Djurica D, Ren J, Holt RR, Feng X, Carlson CR, Shindel AW, Keen CL, Hackman RM, A single intake of a resveratrol-arginine conjugate improves microvascular function compared to trans-resveratrol in postmenopausal women, PharmaNutrition, 2016; 4:132-138

 https://doi.org/10.1016/j.phanu.2016.05.002

11. Ngoumen DJN, Mandob DE, Ella FA, Ambamba BDA, Nanhah JVK, Fonkoua M, Ngondi JL, Flavonoid-enriched extract of Autranella congolensis (Sapotaceae) protects against aluminium chloride-mediated Alzheimer’s disease-like oxidative stress in rats through the antioxidant properties, Metabolic Brain Disease, 2023; 38:1025-1034 https://doi.org/10.1007/s11011-022-01142-x PMid:36522491

12. Walf AA, Frye CA, The use of the elevated plus maze as an assay of anxiety-related behavior in rodents, Nature Protocols, 2007; 2:322-328 https://doi.org/10.1038/nprot.2007.44 PMid:17406592 PMCid:PMC3623971

13. Shoji H, Miyakawa T, Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test, Molecular Brain, 2021; 14:34 https://doi.org/10.1186/s13041-020-00721-2 PMid:33588907 PMCid:PMC7885464

14. Sharma S, Rakoczy S, Brown-Borg H, Assessment of spatial memory in mice, Life Sciences, 2010; 87:521-536 https://doi.org/10.1016/j.lfs.2010.09.004 PMid:20837032 PMCid:PMC6457258

15.  Wilbur KM, Bernheim F, Shapiro OW, The thiobarbituric acid reagent as a test for the oxidation of unsaturated fatty acids by various agents, Archives of Biochemistry, 1949; 24:305-313

16. Ellman GL, Tissue sulfhydryl groups, Archives of Biochemistry and Biophysics, 1959; 82:70-77 https://doi.org/10.1016/0003-9861(59)90090-6 PMid:13650640

17. Sinha AK, Colorimetric assay of catalase, Analytical Biochemistry, 1972; 47:389-394 https://doi.org/10.1016/0003-2697(72)90132-7 PMid:4556490

18. Misra HP, Fridovich I, The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase, Journal of Biological Chemistry, 1972; 247:3170-3175 https://doi.org/10.1016/S0021-9258(19)45228-9 PMid:4623845

19. Flohe L, Gunzler WA, Assays of glutathione peroxidase, Methods in Enzymology, 1984; 105:114-121 https://doi.org/10.1016/S0076-6879(84)05015-1 PMid:6727659

20. Pritam P, Deka R, Bhardwaj A, Srivastava R, Kumar D, Jha AK, Jha NK, Villa C, Jha SK, Antioxidants in Alzheimer’s Disease: Current Therapeutic Significance and Future Prospects, Biology, 2022; 11:212 https://doi.org/10.3390/biology11020212 PMid:35205079 PMCid:PMC8869589

21. Kamaljeet, Singh S, Gupta GD, Aran KR, Emerging role of antioxidants in Alzheimer’s disease: Insight into physiological, pathological mechanisms and management, Pharmaceutical Science Advances, 2024; 2:100021 https://doi.org/10.1016/j.pscia.2023.100021 PMid:41550171 PMCid:PMC12709879

22. Voss JL, Bridge DJ, Cohen NJ, Walker JA, A closer look at the hippocampus and memory, Trends in Cognitive Sciences, 2017; 21:577-588 https://doi.org/10.1016/j.tics.2017.05.008 PMid:28625353 PMCid:PMC5659202

23. Singh A, Kukreti R, Saso L, Kukreti S, Oxidative Stress: A Key Modulator in Neurodegenerative Diseases, Molecules, 2019; 24:1583 https://doi.org/10.3390/molecules24081583 PMid:31013638 PMCid:PMC6514564

24. Dey M, Singh RK, Chronic oral exposure of aluminum chloride in rats modulates molecular and functional neurotoxic markers relevant to Alzheimer’s disease, Toxicology Mechanisms and Methods, 2022; 32:616-627 https://doi.org/10.1080/15376516.2022.2058898 PMid:35341471

25. Wang Y, Branicky R, Noë A, Hekimi S, Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling, Journal of Cell Biology, 2018; 217:1915-1928 https://doi.org/10.1083/jcb.201708007 PMid:29669742 PMCid:PMC5987716

26. Akamba BDA, Pieben CQN, Kenassi MBN, Ebouel FLE, Nanhah JVK, Ella FA, Ngoumen DJN, Talla RM, Mandob DE, Ngondi J, In silico pharmacological study of lacourtianal, a new terpenoid isolated from the stem bark of Chrysophyllum lacourtianum De Wild (Sapotaceae) against Alzheimer’s disease, Journal of Drug Delivery and Therapeutics, 2023; 13:84-90 https://doi.org/10.22270/jddt.v13i12.6322

27. Piebeng CQN, Akamba BDA, Ella FA, Injoh AN, Ngoumen DJN, Mandob DE, Ngondi JL, In silico anti-Alzheimer potential of bioactive compounds in fungi from the African Natural Products Database, Journal of Drug Delivery and Therapeutics, 2024; 14:103-112 https://doi.org/10.22270/jddt.v14i1.6250

28. Krüger M, Arkus W, Manfred I, Daniela G, The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure, Nutrients, 2019; 11:1679 https://doi.org/10.3390/nu11071679 PMid:31336573 PMCid:PMC6683098

29.  Takashi K, Kameishi M, Nanda M, Taketoshi O, Kunio T, Lysine and arginine reduce the effects of cerebral ischemic insults and inhibit glutamate-induced neuronal activity in rats, Frontiers in Integrative Neuroscience, 2010; 4:18-22

30. Song-Feng C, Meng-Xian P, Jun-Chun T, Jing C, Dan Z, Ya Z, Hua-Bao L, Rui L, Yang Z, Zhi-Feng Z, Juan C, Rui-Xue L, Shi-Fang L, Huan-Ting L, Ze-Fen W, Qi W, Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury, Molecular Brain, 2020; 13:63 https://doi.org/10.1186/s13041-020-00601-9 PMid:32321555 PMCid:PMC7175589

31. Karami M, Geravand S, Rahimpour M, Protective Effect of L-Arginine in an Animal Model of Alzheimer’s Disease Induced by Intra-Hippocampal Injection of AlCl3, Neurology India, 2022; 70:548-553 https://doi.org/10.4103/0028-3886.344672 PMid:35532618