Pharmacognosy Magazine

: 2022  |  Volume : 18  |  Issue : 77  |  Page : 128--132

Evaluation of the antidepressant-like activity of the aqueous extract of Crataegus aronia

Hasan Saeed Alamri 
 Department of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia

Correspondence Address:
Hasan Saeed Alamri
Department of Medicine, College of Medicine, King Khalid University, 4742 Almuruj District, Abha 62527
Saudi Arabia


Background: Crataegus aronia L. Syn: Azarolus (C. aronia) is a hawthorn species and a perennial bush native to Mediterranean regions. It is recognized for its high polyphenol content and potent antioxidant effects. Research was conducted to test the antidepressant activities of an aqueous extract of C. aronia in a chronic, unpredictable, mild stress-induced rat model. Materials and Methods: Thirty-two adult Wistar male rats were divided into four groups: A control group (no stress and no treatment), stress-model group (stress and no treatment), fluoxetine-treated stress group (stress and fluoxetine treatment), and C. aronia-treated stress group (stress and C. aronia treatment). Urine samples were collected at 0, 21, 36, and 51 days. Enzyme-linked immunosorbent assay kits were used to assess serotonin, norepinephrine (NE), and dopamine (DA) levels. Results: There was a decrease in serotonin levels 3 weeks after stress exposure, but urinary NE and DA levels increased. C. aronia significantly (P < 0.001) reversed the depressive-like symptoms in the rats according to the increased urinary levels of serotonin. Moreover, C. aronia also reduced urinary levels of urinary NE and DA. The neuromodulatory effects of C. aronia were comparable to that of fluoxetine. Conclusion: With its active ingredients of anthocyanins and procyanidins, C. aronia exhibits significant antidepressant-like activity in validated stressed rats, which may be related to its neuromodulatory effects on central monoamines.

How to cite this article:
Alamri HS. Evaluation of the antidepressant-like activity of the aqueous extract of Crataegus aronia.Phcog Mag 2022;18:128-132

How to cite this URL:
Alamri HS. Evaluation of the antidepressant-like activity of the aqueous extract of Crataegus aronia. Phcog Mag [serial online] 2022 [cited 2022 Dec 5 ];18:128-132
Available from:

Full Text


Based on the findings of this investigation, Crataegus aronia showed antidepression-like action in chronic unpredictable mild stress-induced depression in rats. These effects were probably due to the modulation of central neurotransmitter levels and inhibition of oxidative stress by the synergistic action of various phytoconstituents of C. aronia. Further investigations in vivo are required to support these findings and to investigate the exact mechanisms of these antidepressant activities.


Abbreviations used: CUMS: Chronic unpredictable mild stress; CNS: Central nervous system; 5HT: 5-Hydroxytryptamine; DA: dopamine; NE: Norepinephrine; AECA: Aqueous extract of Crataegus aronia; BDNF: Brain-derived neurotrophic factor; MDD: Major depressive disorder; ELISA: Enzyme-linked immunosorbent assay; WHO: World Health Organization; dBA: Decibel A scale; ECM: Research Ethics Committee; DDDW: De-ionized double distilled water; SEM: Standard error of the mean; ANOVA: Analysis of variance.


Depression is a major concern, and the World Health Organization (WHO) predicts that almost 450 million individuals suffer from depressive disorders worldwide.[1] The WHO rated major depressive disorder (MDD) as third among the major causes of healthcare burden in 2008, and it is expected to rise to first by 2030.[1] It is a complex illness that expresses in a variety of ways at the psychological, behavioral, and physiological levels.[2] The severity of depression is linked to increased treatment costs, treatment efficiency, unemployment, disability, and decreased work performance.[3] The underlying pathology of MDD development is still unknown, and existing treatments are ineffective in many patients. A full grasp of the pathophysiological process is necessary for efficient therapy and disease resolution.[4] The failure of most antidepressant medications highlights the enormous burden and negative impact of depression on individuals, communities, and economies.

Researchers confront major challenges due to the complex nature of MDD, which is frequently linked to other medical conditions. Over the last two decades, antidepressant therapy for MDD has grown in quantity and popularity. However, this tendency has sparked some debate as the therapies' long-term safety and effectiveness have been questioned. Currently available antidepressants have significant downsides, including moderate efficacy, resistance, a slow onset of effect, significant withdrawal symptoms, issues with overdose safety, and dangers during pregnancy and breastfeeding.[5],[6]

The growing understanding of mood disorders and interest in developing more potent and safer antidepressants have led to a search for many natural products.[7] In the history of psychiatry, natural products have played a significant role and appear to be reasonable options for depressed patients who prefer an approach based on natural products.[7] Natural medications such as S-adenosyl-L-methionine, omega-3 fatty acids, and St. John's wort may be valuable supplements to the pharmaceutical arsenal for mood disorders as both monotherapies and adjuvant therapies.[8],[9]

Crataegus is a plant genus in the Rosaceae family and is commonly known as hawthorn. It includes several hundred species of bushes and trees that are native to the temperate climatic zones of the Northern Hemisphere in Asia, North America, North Africa, and Europe. Crataegus species are recognized for having high polyphenol content and some of the most powerful antioxidant effects of any plant species.[10],[11] Correspondingly, there has been a resurgence in scholarly interest in Crataegus in recent years, resulting in numerous research reports on its antioxidant effects.[12]

Despite the many species of hawthorn found worldwide, only a few have been investigated and used clinically for treating depression, including Crataegus pinnatifida and Crataegus monogyna.[13],[14],[15],[16] Crataegus aronia syn. Azarolus (L) (C. aronia) is one of the most widespread types of hawthorn and inhabits the mountains of the Mediterranean region. It has been used in folk medicine for many conditions, such as impotence, cardiovascular disease, diabetes, and cancer.[10],[17] Various extracts of C. aronia leaves reveal the presence of different triterpenoids (euscaphic acid, jacaranoic acid, 2oxopomolic acid, and arjunic acid) and flavonoids (epicatechin, 4”'acetylvitexin2”Orhamnoside, vitexin2”Orhamnoside, and vitexin).[18],[19],[20]

Polyphenols are abundant in C. aronia, and a growing number of epidemiological studies suggest their use in treating neuropsychiatric and neurodegenerative disorders. In addition, animal experiments have revealed that foods high in polyphenols can improve cognitive performance.[21] To the best of our knowledge, there has been no research on the antidepressant effects of C. aronia. Therefore, we designed an experiment to evaluate the impact of an aqueous extract of C. aronia (AECA) on urinary neurotransmitter levels in experimental rats using a chronic stress-induced model to induce depression.

 Materials and Methods


Enzyme-linked immunosorbent assay (ELISA) assay kits for serotonin 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) were purchased from Abnova (CA, USA). Fluoxetine (Prozac, fluoxetine hydrochloride equivalent to 20-mg fluoxetine) was purchased from a local pharmacy. Whole specimens of fresh C. aronia (flowers, leaves, and stems) were bought from a farmers' market in Jordan. The location where it was collected place is situated at 31.963158° N and 35.930359° E, and the specimen was identified by an expert taxonomist. An authentic voucher specimen (067-CA/KKU/2020) has been deposited in the Herbarium and Biological Specimen Department of King Khalid University for future reference. The experiments were done at the physiology labs of King Khalid University, Saudi Arabia.

Preparation of aqueous extract of Crataegus aronia

The entire plant of C. aronia was air-dried, and an extract was obtained in the pharmacognosy laboratory. The dried plant material was ground into a powder and soaked for 3 days at 37°C with distilled water (100 g/300 mL, w/v). The AECA was filtered through Whatman No. 1 paper under vacuum and evaporated under reduced pressure in a rotary evaporator. The resulting residue (40 g) was then stored at 4°C. The residue was reconstituted in double-distilled de-ionized water, filtered through 0.2-μM filters, and then stored in a refrigerator until the experimental study.[22] The aqueous extract was subjected to preliminary phytochemical analysis to detect plant components using standard chemical tests.[23]

Experimental animals

The experimental animals were 32 adult Wistar male rats from a similar lineage and genetic pool, which were obtained from the animal house at King Khalid University. Their age was 6 months, and they weighed 230–250 g. The animals were housed in polypropylene mouse cages with standard dimensions (50 cm × 26 cm × 16 cm) in groups of 4 rats per cage. The cages were kept at 25°C ± 1°C with a standard 12-h day/night cycle. All experimental protocols were approved by King Khalid University's Research Ethics Committee (#20-0862) and carried out while following the National Institutes of Health's guidelines for the care and use of laboratory animals. Every effort has been made to ensure minimal animal suffering and a minimal number of animals used.

Chronic unpredictable mild stress-induced depression model

Chronic unpredictable mild stress (CUMS) was used to induce depression in rats [Table 1] as follows: Cage tilting and damp sawdust for 24 h (200 mL of water per individual cage, which is enough to make the sawdust bedding wet); 5 min of cold swimming in water at 4°C; noise for 1 h (alternative periods of 60-Decibel A scale noise for 10 min and 10 min of silence); 5 min of thermal stimulation in an experimental room at 50°C; 48 h of food deprivation and 24 h of water deprivation; 15 electric shocks to the foot (15 mA, one shock/5 s, 10-s duration); a 1-min tail pinch; and restricted movement for 4 h. On each day, one stressor was applied, and the complete stress procedure lasted 3 weeks, with the stressors being delivered in entirely random order.[24] The healthy control group of rats was accommodated undisturbed in another experiment room under the same circumstances.{Table 1}

Experimental design

After 2 weeks of habituation, all of the rats were divided at random into four groups (n = 8). The control group received distilled water and normal rat diet for 51 days (no stress and no treatment), and the stress-model group was stressed for 21 days and then received distilled water and normal rat diet for the next month. The fluoxetine-treated stress group was stressed for 21 days, received fluoxetine daily (2 mg/kg/day, i.p.) for the next month, and was kept on a normal rat diet. The C. aronia-treated stress group was stressed for 21 days and then received the AECA orally (10 mg/kg/day, p.o.) for the next month. The pharmacological dose was selected from a previous experimental study, which reported that whole-plant AECA has no toxic effects when administered at 2000 mg/kg.[25]

Urine collection and biochemical analysis

Urine samples were collected from rats at days 0, 21 (after stress induction), 36 (15 days after stress induction), and 51 (1 month after stress induction) using metabolic cages (1 rat/cage). Collected urine was filtered using 0.2-μm filters, and then special ELISA kits (Abnova, USA) were used for the determination of 5-HT (KA 1894), NE (Cat No. KA1891), and DA (Cat NO. KA1887).[26]

Statistical analysis

The data were analyzed using GraphPad Prism version 8.0 for Windows (GraphPad Software, San Diego, CA, USA), and the results are reported as the mean ± standard error of the mean. Two-way analysis of variance using Tukey's multiple comparison test was employed to evaluate the statistically significant changes between the treatments and intervals, and P < 0.001 was considered statistically significant.


Phytochemical analysis of C. aronia indicated the presence of flavonoids, polysaccharides, terpenoids, tannins, catechins, monoterpenes, proanthocyanidins, and steroids. The levels of 5-HT, NE, and DA were evaluated as potential urinary biomarkers for CUMS-induced depression in rats. The ELISA method was used to measure the urinary neurotransmitter levels. The concentration of 5-HT was significantly lower in the urine samples of CUMS-induced animals than in normal rats, as shown in [Figure 1]. Lower urinary levels of 5-HT were also observed in the CUMS-exposed treatment groups than in controls. However, long-term therapy with AECA significantly increased the concentration of 5-HT after 36 and 51 days (P < 0.001) compared with CUMS-stressed rats. The 5-HT concentration in the fluoxetine group was also significantly higher after 36 and 51 days (P < 0.001) than in the CUMS control group.{Figure 1}

[Figure 2] and [Figure 3] show a significant rise in the urinary levels of NE and DA after 21 days of CUMS induction compared to the unstressed group. When comparing the CUMS-stressed group to the treatment group, we found a sustained and substantial increase in NE and DA levels. Both AECA and fluoxetine-treated groups exhibited a significant decrease in NE [[Figure 2], P < 0.001] and DA levels [[Figure 3]; P < 0.001] after 36 and 51 days.{Figure 2}{Figure 3}


Urine is widely considered the recommended body fluid for measuring neurotransmitters because of its non-invasive collection technique and the fact that it is the main mechanism of neurotransmitter excretion.[27] In this study, neurotransmitters were detected with commercially available ELISA kits. Compared to blood sampling, urinary samples are more appropriate for collection, especially for small experimental animals. The non-invasive sampling method could prevent interference in neuropharmacological studies of experimental animals.[28]

ELISA provides an appropriate and robust way of investigating urinary monoamines, including 5-HT. A recent literature review indicates that neurotransmitters released in urine could be used as biomarkers of nervous system function.[29] Several studies have consistently shown a significant relationship of depressive disorders with urinary monoamine excretion levels, thus suggesting that they could help in diagnosing and managing MDD patients.[30]

CUMS is the most widely used, reliable, and effective model currently available to induce depression in animals. Several experimental studies have confirmed that the CUMS model can cause depression-like behavior in experimental rats.[31],[32],[33] In the current experiment, CUMS-induced depressive rats showed higher levels of DA and NE and lower levels of 5-HT. After 21 days of applying the CUMS procedure, the altered levels of these urinary monoamines could be associated with CUMS-induced depression.[34]

The administration of AECA can effectively reduce elevated levels of DE and NE while increasing 5-HT levels, and the changes were consistent with previous studies in animal models of depression. CUMS has a significant effect on monoaminergic activity in rats.[35] The brain monoamine systems play a significant role in depressive disorders and are supported by antidepressants' mechanisms of action.[36] Reduced levels of monoamine neurotransmitters in the central nervous system, especially with dysfunction of the serotonin system, have a major role in the pathogenesis of depression.[37] The concept of using antidepressants as the first-line clinical treatment of MDD involves enhancing levels of neurotransmitters and monoamine receptors.[38]

In the current research, monoamine neurotransmitter levels were significantly altered in the CUMS-stressed rats, but oral AECA administration significantly reversed the clinical observations generated by CUMS and reversed the altered levels to levels comparable to those of fluoxetine-administered rats. As hypothesized, this observation suggests that these normalizations of neurotransmitter expression may produce the antidepressant-like effects of AECA through increased central monoamine neurotransmitters levels. The use of phytotherapy-based nutraceuticals to treat MDD is an important strategy for potentially improving clinical outcomes.[39] One possible mechanism of action of AECA is the attenuation of oxidative stress produced during CUMS-induced depression by polyphenolic compounds, such as flavonoids (mainly anthocyanins and procyanidins).[40],[41] Polyphenols have potent neuroprotective effects and are suggested to improve depression by increasing monoamine neurotransmitter levels, which may occur through the up-regulation of brain-derived neurotrophic factor expression.[42],[43]

The antidepressant-like effect of AECA in this study is consistent with other investigations demonstrating the antidepressant and antioxidant effects of Crataegus species, which are rich in polyphenols.[44],[45] Lim et al. showed that 1 month of freely drinking phenolic-rich Crataegus extract up-regulates central 5-HT levels but not noradrenaline, which may be associated with anxiolytic-like and antidepressant-like effects.[15] Finally, the current study suggests that the antidepressant effect of AECA is partly due to the modulation of 5-HT, DA, and NE. However, the exact mechanism needs more examination, and the exact targets of the antidepressant-like effects of AECA remain unknown, thus requiring further research.


The present study provides the first proof that AECA, which has active ingredients of anthocyanins and procyanidins, exhibits significant antidepressant-like activity in a validated CUMS-induced depression model. These effects may be related to its neuromodulatory effects on central monoamine levels such as NE, DA, and 5-HT. The high polyphenolic contents in C. aronia could be linked to its mechanism of action, which reduced CUMS-induced oxidative stress. For further study, the active phytoconstituents should be isolated and identified from the aqueous extract to determine what is responsible for the effects. In addition, other potential mechanisms could be implicated, and safety studies are required. The current study indicates that C. aronia deserves further investigation as a potential antidepressant and could pave the way to develop a new phytotherapy.


The author gratefully acknowledges Dr. Abdullah Shatoor, Professor of Cardiology at King Khalid University, who has published several research papers on the medicinal applications of C. aronia, for his advice and for supplying us with the C. aronia herb. I also thank Mr. Mahmoud Al-Khatib and Mr. Hussein Sakr, who are both lecturers at the Department of Physiology, King Khalid University, for their technical assistance in conducting the research.

Financial support and sponsorship

This study was financed by the Scientific Research Deanship, King Khalid University, Saudi Arabia.

Conflicts of interest

The author declares no conflicts of interest.


1Malhi GS, Mann JJ. Depression. Lancet 2018;392:2299-312.
2Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health 2013;34:119-38.
3Birnbaum HG, Kessler RC, Kelley D, Ben-Hamadi R, Joish VN, Greenberg PE. Employer burden of mild, moderate, and severe major depressive disorder: Mental health services utilization and costs, and work performance. Depress Anxiety 2010;27:78-89.
4Ménard C, Hodes GE, Russo SJ. Pathogenesis of depression: Insights from human and rodent studies. Neuroscience 2016;321:138-62.
5Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: A critical review of the literature. Psychother Psychosom 2016;85:270-88.
6Alqahtani AM, Kumarappan C, Kumar V, Srinivasan R, Krishnaraju V. Understanding the genetic aspects of resistance to antidepressants treatment. Eur Rev Med Pharmacol Sci 2020;24:7784-95.
7Sarris J, Kavanagh DJ, Byrne G. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. J Psychiatr Res 2010;44:32-41.
8Mischoulon D. Update and critique of natural remedies as antidepressant treatments. Obstet Gynecol Clin North Am 2009;36:789-807.
9Nabavi SM, Daglia M, Braidy N, Nabavi SF. Natural products, micronutrients, and nutraceuticals for the treatment of depression: A short review. Nutr Neurosci 2017;20:180-94.
10Ljubuncic P, Portnaya I, Cogan U, Azaizeh H, Bomzon A. Antioxidant activity of Crataegus aronia aqueous extract used in traditional Arab medicine in Israel. J Ethnopharmacol 2005;101:153-61.
11Nabavi SF, Habtemariam S, Ahmed T, Sureda A, Daglia M, Sobarzo-Sánchez E, et al. Polyphenolic composition of Crataegus monogyna Jacq.: From chemistry to medical applications. Nutrients 2015;7:7708-28.
12Keser S, Celik S, Turkoglu S, Yilmaz Ö, Turkoglu I. The investigation of some bioactive compounds and antioxidant properties of hawthorn (Crataegus monogyna subsp. monogyna Jacq). J Intercult Ethnopharmacol 2014;3:51-5.
13Doron R, Lotan D, Einat N, Yaffe R, Winer A, Marom I, et al. A novel herbal treatment reduces depressive-like behaviors and increases BDNF levels in the brain of stressed mice. Life Sci 2014;94:151-7.
14Avitsur R, Paley S, Franko M, Wolff N, Eyal N, Doron R. Escitalopram or novel herbal treatments differentially alter cytokine and behavioral responses to immune challenge. J Neuroimmunol 2017;309:111-8.
15Lim DW, Han T, Jung J, Song Y, Um MY, Yoon M, et al. Chlorogenic acid from hawthorn berry (Crataegus pinnatifida Fruit) prevents stress hormone-induced depressive behavior, through monoamine oxidase B-reactive oxygen species signaling in hippocampal astrocytes of mice. Mol Nutr Food Res 2018;12:e1800029.
16Zanganenejad Z, Ahmadynasab M, Setorki M. Effect of Crataegus monogyna extract on anxiety, depression, and pain in streptozotocin-induced diabetic rats. J Diabetes Nurs 2018;6:539-49.
17Ali-Shtayeh MS, Yaniv Z, Mahajna J. Ethnobotanical survey in the Palestinian area: A classification of the healing potential of medicinal plants. J Ethnopharmacol 2000;73:221-32.
18Mahmud SA, Al-Habib OA, Bugonl S, Clericuzio M, Vidari G. A new ursane-type triterpenoid and other constituents from the leaves of Crataegus azarolus var. Aronia. Nat Prod Commun 2016;11:1637-9.
19Abu-Gharbieh E, Shehab NG. Therapeutic potentials of Crataegus azarolus var. eu- azarolus Maire leaves and its isolated compounds. BMC Complement Altern Med 2017;17:218.
20Takahashi A, Shimizu H, Okazaki Y, Sakaguchi H, Taira T, Suzuki T, et al. Anthocyanin-rich phytochemicals from Aronia fruits inhibit visceral fat accumulation and hyperglycemia in high-fat diet-induced dietary obese rats. J Oleo Sci 2015;64:1243-50.
21Sureda A, Tejada S. Polyphenols and depression: From chemistry to medicine. Curr Pharm Biotechnol 2015;16:259-64.
22Shatoor AS, Soliman H, Al-Hashem F, Gamal BE, Othman A, El-Menshawy N. Effect of Hawthorn (Crataegus aronia syn. Azarolus (L)) on platelet function in albino Wistar rats. Thromb Res 2012;130:75-80.
23Bomfim EM, Coelho AA, Silva MC, Marques EJ, Vale VL. Phytochemical composition and biological activities of extracts from ten species of the family Melastomataceae Juss. Braz J Biol 2021;82:e242112.
24Willner P. Chronic mild stress (CMS) revisited: Consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 2005;52:90-110.
25Shatoor AS. Acute and sub-acute toxicity of Crataegus aronia Syn. azarolus (L.) whole plant aqueous extract in Wistar rats. Am J Pharmacol Toxicol 2011;6:37-45.
26Su ZH, Li SQ, Zou GA, Yu CY, Sun YG, Zhang HW, et al. Urinary metabonomics study of anti-depressive effect of Chaihu-Shu-Gan-San on an experimental model of depression induced by chronic variable stress in rats. J Pharm Biomed Anal 2011;55:533-9.
27Lepschy M, Rettenbacher S, Touma C, Palme RG. Excretion of catecholamines in rats, mice and chicken. J Comp Physiol B 2008;178:629-36.
28Zhao L, Zhang Z, Zhou M, Gou X, Zeng Y, Song J, et al. A urinary metabolomics (GC-MS) strategy to evaluate the antidepressant-like effect of chlorogenic acid in adrenocorticotropic hormone-treated rats. RSC Adv 2018;8:9141-51.
29Marc DT, Ailts JW, Campeau DC, Bull MJ, Olson KL. Neurotransmitters excreted in the urine as biomarkers of nervous system activity: Validity and clinical applicability. Neurosci Biobehav Rev 2011;35:635-44.
30Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008;69 Suppl E1:4-7.
31Sequeira-Cordero A, Salas-Bastos A, Fornaguera J, Brenes JC. Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats. Sci Rep 2019;9:17403.
32Geng C, Guo Y, Wang C, Liao D, Han W, Zhang J, et al. Systematic impacts of chronic unpredictable mild stress on metabolomics in rats. Sci Rep 2020;10:700.
33Antoniuk S, Bijata M, Ponimaskin E, Wlodarczyk J. Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neurosci Biobehav Rev 2019;99:101-16.
34Chen YP, Wang C, Xu JP. Chronic unpredictable mild stress induced depression-like behaviours and glutamate-glutamine cycling dysfunctions in both blood and brain of mice. Pharm Biol 2019;57:280-6.
35Abdul Shukkoor MS, Baharuldin MT, Mat Jais AM, Mohamad Moklas MA, Fakurazi S. Antidepressant-like effect of lipid extract of Channa striatus in chronic unpredictable mild stress model of depression in rats. Evid Based Complement Alternat Med 2016;2016:2986090.
36Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry 2017;4:409-18.
37Ming QS, Zhang Y, Chai QL, Chen HY, Hou CJ, Wang MC, et al. Interaction between a serotonin transporter gene promoter region polymorphism and stress predicts depressive symptoms in Chinese adolescents: A multi-wave longitudinal study. BMC Psychiatry 2013;13:142.
38Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol 2015;95:81-97.
39Alirezalu A, Ahmadi N, Salehi P, Sonboli A, Alirezalu K, Mousavi Khaneghah A, et al. Physicochemical characterization, antioxidant activity, and phenolic compounds of hawthorn (Crataegus spp.) fruits species for potential use in food applications. Foods 2020;9:436.
40Bahri-Sahloul R, Ammar S, Fredj RB, Saguem S, Grec S, Trotin F, et al. Polyphenol contents and antioxidant activities of extracts from flowers of two Crataegus azarolus L. varieties. Pak J Biol Sci 2009;12:660-8.
41Sun Q, Jia N, Ren F, Li X. Grape seed proanthocyanidins improves depression-like behavior by alleviating oxidative stress and NLRP3 activation in the hippocampus of prenatally-stressed female offspring rats. J Histotechnol 2021;44:90-8.
42Huang XX, Ren Q, Song XY, Zhou L, Yao GD, Wang XB, et al. Seven new sesquineolignans isolated from the seeds of hawthorn and their neuroprotective activities. Fitoterapia 2018;125:6-12.
43Rjeibi I, Zaabi R, Jouida W. Characterization of polysaccharides extracted from pulps and seeds of Crataegus azarolus L. var. aronia: Preliminary structure, antioxidant, antibacterial, α-amylase, and acetylcholinesterase inhibition properties. Oxid Med Cell Longev 2020;2020:1903056.
44Diaz-Veliz G. Antidepressant effect of hydroalcoholic extract from Crataegus spp. in Sprague Dawley rats using an animal stress model based on movement restriction. Rev Farmacol Chile 2015;8:19-25.
45Ibrahim SE, Al-Saeed HF, Yousuf AF. The possible mitigating effect of hawthorn on some cold stress-induced changes in rats. Al Azhar Assiut Med J 2021;19:73-9.