Neuroprotection and anxiety like behavior reduction of Allium hirtifolium and Astragalus hamosus in the Aβ-injected rat

Document Type : Original paper


1 Traditional Medicine and Materia Medica Research Center and Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.


Background and objectives:Traditional medicine is an important approach to achieve new therapeutic strategies in basic and clinical pharmacology. Allium hirtifolium Boiss. and Astragalus hamosus L. have been mentioned in Iranian Traditional Medicine references for a kind of dementia with features and symptoms similar to those of Alzheimer's disease (AD). In the present study, the neuroprotective effect of these herbs has been evaluated as new therapies in neurotoxicity model.
Methods: Two separate groups of rats were fed with A. hirtifolium or A. hamosus extract (100 mg/kg/day) from 1 week before amyloid beta (Aβ) injection, for 16 consecutive days. One day after the last oral administration, behavioral test was done. The effect of these two extracts were assessed in anxiety-like behavior test using elevated plus maze. Furthermore, molecular pathways involved in apoptosis were assessed by Western blotting analysis.
Results: The results showed that oral administration of both A. hirtifolium and A. hamosus decreased anxiety-like behavior and ameliorated the effect on apoptosis factors including Bax, Bcl-2 and caspase-3 in the rats with intra-hippocampal injection of Aβ.
Conclusion: The results of this study revealed the potential neuroprotective properties of A. hirtifolium and A. hamosus as herbal remedies that could play a role in fostering healthy aging and be considered as useful candidates in decreasing AD related symptoms.


[1] Hart D, Craig D, Compton S, Critchlow S, Kerrigan B, McIlroy S, Passmore AP. A retrospective study of the behavioural and psychological symptoms of mid and late phase Alzheimer's disease. Int J Geriatr Psych. 2003; 18(11): 1037-1042.
[2] Alzheimer’s Association. Alzheimer's disease facts and figures. Alzheimers Dement. 2015; 11(3): 1-83.
[3] Desai AK, Grossberg GT. Recognition and management of behavioral disturbances in dementia. Prim Care Companion J Clin Psychiatry. 2001; 3(3): 93-109.
[4] Sadowsky CH, Galvin JE. Guidelines for the management of cognitive and behavioral problems in dementia. J Am Board Fam Med. 2012; 25(3): 350-366.
[5] Kraus CA, Seignourel P, Balasubramanyam V, Snow AL, Wilson NL, Kunik ME, Schulz PEStanley MA. Cognitive-behavioral treatment for anxiety in patients with dementia: two case studies. J Psychiatr Pract. 2008; 14(3): 186-192.
[6] Goldsworthy MR, Vallence AM. The Role of ß-amyloid in Alzheimer’s Disease-related neurodegeneration. J Neurosci. 2013; 33(32): 12910-12911.
[7] Miguel-Hidalgo JJ, Paul IA, Wanzo V, Banerjee PK. Memantine prevents cognitive impairment and reduces Bcl-2 and caspase 8 immunoreactivity in rats injected with amyloid β 1–40. Eur J Pharmacol. 2012; 692(1): 38-45.
[8] Kim SE, Ko IG, Kim BK, Shin MS, Cho S, Kim CJ, Baek SSLee EKJee YS. Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus. Exp Gerontol. 2010; 45(5): 357-365.
[9] Shi L, Chen J, Yang J, Pan T, Zhang S, Wang Z. MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res. 2010; 1352: 255-264.
[10] Zare N, Khalifeh S, Khodagholi F, Shahamati SZ, Motamedi F, Maghsoudi N. Geldanamycin reduces Aβ-associated anxiety and depression, concurrent with autophagy provocation. J Mol Neurosci. 2015; 57(3): 317-324.
[11] Anekonda TS, Reddy PH. Can herbs provide a new generation of drugs for treating Alzheimer's disease? Brain Res Rev. 2005; 50(2): 361-376.
[12] Kim HG, Oh MS. Herbal medicines for the prevention and treatment of Alzheimer's disease. Curr Pharm Design. 2012; 18(1): 57-75.
[13] Chashti HAK. Exir-e-Azam. 1st ed. Tehran: University of Medical Science, Institute for Islamic and Complementary Medicine, 2007.
[14] Rhazes. Al-hawi. 1st ed. Afsharipour S, (Trans.). Thehran: Academy of medical sciences publication, 2005.
[15] Avicenna. The Canon of medicine. 2nd ed. Sharafkandi A, Ed. Tehran: Soroush press, 1997.
[16] Aghili khorasani MH. Makhzan-al-advia. 1st ed. Shams Ardekani MR, Rahimi R, Farjadmand F, Eds. Tehran: Rahe kamal, 2009.
[17] Fritsch RM, Gurushidze M, Jedelska J, Keusgen M. More than apretty face-ornamental “drumstick onions” of Allium subg. melanocrommyum are also potential medicinal plants. Planta Med. 2007; 73(09): 26-59.
[18] Fritsch RM, Abbasi M. A taxonomic review of Allium subg. melanocrommyum in Iran. 1st ed. Gatersleben:IPK Gatersleben, 2013.
[19] Sobolewska D, Michalska K, Podolak I, Grabowska K. Steroidal saponins from the genus Allium. Phytochem Rev. 2016; 15(1): 1-35.
[20] Shahgholi H, Vazirimehr MRV, Hosein Talaei G, Rigi K. Effect bulb size and two specie mooseer to yield components bulb percent allicin in weather mashha. J Bio & Env Sci. 2014; 5(1):236-242.
[21] Kannappan R, Gupta SC, Kim JH, Reuter S, Aggarwal BB. Neuroprotection by spice-derived nutraceuticals: you are what you eat! Mol Neurobiol. 2011; 44(2): 142-159.
[22] Stankevičius M, Akuņeca I, Jãkobsone I, Maruška A. Analysis of phenolic compounds and radical scavenging activities of spice plants extracts. Maisto Chemija Ir Technologija. 2010; 44(2): 85-91.
[23] Ghahremani-majd H, Dashti F, Dastan D, Mumivand H, Hadian J, Esna-Ashari M. Antioxidant and antimicrobial activities of Iranian mooseer (Allium hirtifolium Boiss) populations. Hortic Environ Biote. 2012; 53(2): 116-122.
[24] Azadi HG, Ghaffari SM, Riazi GH, Ahmadian S, Vahedi F. Antiproliferative activity of chloroformic extract of Persian Shallot, Allium hirtifolium, on tumor cell lines. Cytotechnology. 2008; 56(3): 179-185.
[25] Krejčová P, Kučerová P, Stafford GI, Jäger AK, Kubec R. Antiinflammatory and neurological activity of pyrithione and related sulfur-containing pyridine N-oxides from Persian shallot (Allium stipitatum). J Ethnopharmacol. 2014; 154(1): 176-182.
[26] Rafieian-kopaei M, Keshvari M, Asgary S, Salimi M, Heidarian E. Potential role of a nutraceutical spice (Allium hirtifolium) in reduction of atherosclerotic plaques. J Herb Med Pharmacol. 2014; 2(2): 23-28.
[27] Mahmoodi M, Hosseini J, Hosseini-Zijoud SM, Mirzaee M, Mirzajani E. The effect of Persian shallot (Allium hirtifolium Boiss.) extract on blood sugar and serum levels of some hormones in diabetic rats. Pak J Pharm Sci. 2013; 26(2): 397-402.
[28] Jafarian A, Ghannadi A, Elyasi A. The effects of Allium hirtifolium Boiss. on cell-mediated immune response in mice. Iran J Pharm Res. 2003; 2(1): 51-55.
[29] Mohammadi S, Zarei M, Mahmoodi M, Zarei MM, Nematian MA. In vivo antinociceptive effects of Persian shallot (Allium hirtifolium) in male rat. Avicenna J Neuro Psycho Physiol. 2015; 2(1): 1-5.
[30] Hooper D, McNair JB, Field H. Useful plants and drugs of Iran and Iraq. 1st ed. Chicago: Field Museum of Natural History, 1937.
[31] Ghahremaninejad F. Two new records of Astragalus species of the sections Anthylloidei DC. and Dissitiflori DC. from Iran. Turk J Bot. 2005; 29(5): 399-402.
[32] Hakim A, Tajuddin, Ghufran A, Nasreen J. Evaluation of anti-inflammatory activity of the pods of Iklil-ul-Malik (Astragalus hamosus Linn.). Indian J Nat Prod Resour. 2010; 1(1): 34-37.
[33] Shojaii A, Motaghinejad M, Norouzi S, Motevalian M. Evaluation of anti-inflammatory and analgesic activity of the extract and fractions of Astragalus hamosus in animal models. Iran J Pharm Res. 2015; 14(1): 263-269.
[34] Kondeva-Burdina M, Krasteva I, Mitcheva M. Effects of rhamnocitrin 4-β-D-galactopyranoside, isolated from Astragalus hamosus on toxicity models in vitro. Pharmacogn Mag. 2014; 10(S3): 487-493.
[35] Handa SS, Khanuja SPS, Longo G, Rakesh DD. Extraction technologies for medicinal and aromatic plants. 3rd ed. Trieste: Earth, Environmental and Marine Sciences and Technologies, 2008.
[36] National Institutes of Health. Guide for care and use of laboratory animals. 6th ed. Bethesda: NIH Publication, 1985.
[37] Bahaeddin Z, Yans A, Khodagholi F, Hajimehdipoor H, Sahranavard S. Hazelnut and neuroprotection: Improved memory and hindered anxiety in response to intra-hippocampal Aβ injection. Nutr Neurosci. In press.
[38] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 3rd ed. San Diego: Academic Press, 2007.
[39] Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc. 2007; 2(2): 322-328.
[40] Zarrindast MR, Khalifeh S, Rezayof A, Rostami P, Sereshki AA, Zahmatkesh M. Involvement of rat dopaminergic system of nucleus accumbens in nicotine-induced anxiogenic-like behaviors. Brain Res. 2012; 1460: 25-32.
[41] Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiat. 2004; 161(1): 109-115.
[42] Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999; 6(2): 99-104.
[43] Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000; 407(6805): 802-809.
[44]  Harkany T, O'Mahony S, Keijser J, Kelly JP, Kónya C, Borostyánkői ZA, Görcs TJZarándi MPenke BLeonard BELuiten PG. β-Amyloid (1-42)-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex. Neurobiol Dis. 2001; 8(4): 667-78.
[45] Revest J, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza P, Abrous DN. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatr. 2009; 14(10): 959-967.
[46] Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacol. 2015; 40(10): 2368-2378.
[47] Hroudová J, Fišar Z, Raboch J. Mitochondrial functions in mood disorders. In: Kocabaşoğlu N, Ed. Mood disorders. Rijeka: InTech, 2013.
[48] Einat H, Yuan P, Manji HK. Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Behav Brain Res. 2005; 165(2): 172-180.
[49] Pirbalouti AG, Ahmadzadeh Y, Malekpoor F. Variation in antioxidant, and antibacterial activities and total phenolic content of the bulbs of mooseer (Allium hirtifolium Boiss.). Acta Agric Slov. 2015; 105(1): 15-22.
[50] Galato D, Ckless K, Susin MF, Giacomelli C, Ribeiro-do-Valle RM, Spinelli A. Antioxidant capacity of phenolic and related compounds: correlation among electrochemical, visible spectroscopy methods and structure-antioxidant activity. Redox Rep. 2001; 6(4): 243-250.
[51] Montine T, Neely M, Quinn J, Beal M, Markesbery W, Roberts L, Morrow JD. Serial review: causes and consequences of oxidative stress in Alzheimer's disease. Free Radic Biol Med. 2002; 33(5): 620-626.
[52] Kelsey NA, Wilkins HM, Linseman DA. Nutraceutical antioxidants as novel neuroprotective agents. Molecules. 2010; 15(11): 7792-7814.
[53] Espín JC, García-Conesa MT, Tomás-Barberán FA. Nutraceuticals: facts and fiction. Phytochemistry. 2007; 68(22): 2986-3008.
[54] Bahadoran Z, Mirmiran P, Azizi F. Dietary polyphenols as potential nutraceuticals in management of diabetes: a review. J Diabetes Metab Disord. 2013; 12(1): 1-9
[55] Gomez-Pinilla F, Nguyen TT. Natural mood foods: the actions of polyphenols against psychiatric and cognitive disorders. Nutr Neurosci. 2012; 15(3): 127-133.
[56] Dias GP, Cavegn N, Nix A, do Nascimento Bevilaqua MC, Stangl D, Zainuddin MSA, Nardi AE, Gardino PF, Thuret S. The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety. Oxid Med Cell Longev. 2012; Article ID 541971.
[57] Aquilano K, Baldelli S, Rotilio G, Ciriolo MR. Role of nitric oxide synthases in Parkinson’s disease: a review on the antioxidant and anti-inflammatory activity of polyphenols. Neurochem Res. 2008; 33(12): 2416-2426.
[58] Kim JG, Koh SH, Lee YJ, Lee KY, Kim Y, Kim S, Lee MKKim SH. Differential effects of diallyl disulfide on neuronal cells depend on its concentration. Toxicology. 2005; 211(1): 86-96.
[59] Li XH, Li CY, Lu JM, Tian RB, Wei J. Allicin ameliorates cognitive deficits ageing-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Neurosci Lett. 2012; 514(1): 46-50.
[60] Li XH, Li CY, Xiang ZG, Zhong F, Chen ZY, Lu JM. Allicin can reduce neuronal death and ameliorate the spatial memory impairment in Alzheimer's disease models. Neurosciences (Riyadh). 2010; 15(4): 237-243.
[61] Li X, Qu L, Dong Y, Han L, Liu E, Fang S, Zhang Y, Wang T. A Review of recent research progress on the Astragalus genus. Molecules. 2014; 19(11): 18850-18880.
[62] Krasteva I, Platikanov S, Nikolov S, Kaloga M. Flavonoids from Astragalus hamosus. Nat Prod Res. 2007; 21(5): 392-395.
[63] Cardoso BR, Ong TP, Jacob-Filho W, Jaluul O, Freitas MIdÁ, Cozzolino SMF. Nutritional status of selenium in Alzheimer's disease patients. Brit J Nutr. 2010; 103(06): 803-806.
[64] Shaw W, Anderson J. Comparative enzymology of the adenosine triphosphate sulphurylases from leaf tissue of selenium-accumulator and non-accumulator plants. Biochem J. 1974; 139(1): 37-42.
[65] Cao C, Wang L, Lin X, Mamcarz M, Zhang C, Bai G, Bai G, Nong JSussman SArendash G. Caffeine synergizes with another coffee component to increase plasma GCSF: linkage to cognitive benefits in Alzheimer's mice. J Alzheimers Dis. 2011; 25(2): 323-335.