Studies on Apigenin and Its Biological and Pharmacological Activity in Brain Disorders

Vishal Kumar; Satyabrata Kundu

doi:10.34172/apb.2022.068

Advanced pharmaceutical bulletin. 12(4):645-648. doi: 10.34172/apb.2022.068

Letter to Editor

Studies on Apigenin and Its Biological and Pharmacological Activity in Brain Disorders

Vishal Kumar, Satyabrata Kundu^,^*

Department of Pharmacology, ISF College of Pharmacy Moga, Punjab 142001 India.

*Corresponding Author: Satyabrata Kundu, Email: satyabratak96@gmail.com

Abstract

Keywords:

Copyright

©2022 The Authors.
This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.

Dear Editor,

Apigenin (4′,5,7-trihydroxyflavone) is a dietary flavonoid that is abundantly present in many fruits, medicinal herbs, vegetables and formally belongs to the flavone sub-class.¹ The best sources of apigenin are parsley, chamomile, celery, artichokes, and oregano.² Apigenin is a compound with low toxicity and multiple beneficial bioactivities. Apigenin has several beneficial effects as an antioxidant, anti-inflammatory, blood pressure reduction, and chemo-preventive.³ Apigenin has an effect in the downregulation of IL-1β and TNF-α; also, it shows anti-inflammatory properties by attenuating the expression of COX-2 and iNOS.¹ At the cellular level, apigenin acts as an inhibitor of several protein-tyrosine and serine-kinases.³ Apigenin has many pharmacological roles as antiphlogistic, antispasmodic, and antibacterial agent, anti-asthmatic, anti-parkinsonism agent (Table 1).⁴

Table 1. Recent studies on apigenin and its biological and pharmacological activities

S. No.	Key outcomes	References
1	Apigenin shows a protective effect in the preclinical model of down syndrome, via reduction of oxidative stress and activation of proliferative and pro-neurogenic genes (KI7, Nestin, Sox2, and PAX6). Apigenin may be a potential therapeutic candidate for the management of down syndrome.	⁵
2	Apigenin reversed decreased cell viability, the activity of sodium pump, increased LDH release, and apoptotic rate in OGD/R injury in rat hippocampal neurons. The finding suggested that it can be a novel therapeutic candidate to improve sodium pump activity.	⁶
3	In the combination of apigenin and trolox, apigenin shows a strong inhibitory effect in H₂O₂ induced ROS production in RAW264.7 cells as well as free radical-induced oxidative damage in erythrocytes than trolox. However, apigenin also exerts a strong inhibitory effect on LPS induced NF-kB/NLRP3/caspase-1 signaling in RAW246.7 cells than trolox. Results suggested that apigenin might be a potent drug candidate for the management of oxidative stress and inflammatory diseases.	⁷
4	AP-SD prospers the nuclear translocation of Nrf2 and increases the expression of Nrf2 as well as target genes HO-1 and NQO-1. It also enhanced the activity of SOD and GSH-Px, and decreased the level of ROS and MDA in a mouse model of AMD. The finding suggested that AP-SD could be an effective compound for the treatment of AMD.	⁸
5	Apigenin and luteolin resist the activation of astrocytes and inhibit the protein and mRNA expression in LPS-induced astrocyte cultured neurons. Apigenin also inhibits the IL-31 and IL-33 via suppression of ERK, NF-kB, and STATE. Similarly, luteolin inhibits IL-31 via suppression of JNK, p38, ERK, NF-kB, and STAT3 in astrocytes. The finding suggested that both apigenin and luteolin have the potential to treat diseases involving astrocyte activation.	⁹
6	Apigenin increased Nrf2 nuclear translocation, GSK-3β phosphorylation, and reduced apoptosis, decrease LDH release, and promote cell viability in both OGD/R cell cultures and a rat model of ischemic-reperfusion. The study suggested that apigenin could be a strong neuroprotective drug candidate.	¹⁰
7	Apigenin significantly delayed peripheral nerve degeneration via inhibiting of degradation of myelin and peripheral axons, and also inhibits the proliferation of Schwann cells. Thus, apigenin can be a novel therapeutic choice for treating peripheral neurodegenerative diseases.	¹¹
8	Apigenin rescues memory deficits and decreases cell viability in hilus, however, it also decreases the release of cytochrome c in the kainic acid-induced rat model of temporal lobe epilepsy. The study suggested that clinically apigenin could reverse memory impairment via anticonvulsant and neuroprotective activity.	¹²
9	Apigenin significantly fettles spatial working memory and decreased degenerative neurons in hilus via complete blockade of caspase 9 and cytochrome c release in Aβ 25-35 induced rat model of Alzheimer disease. The finding suggested that apigenin can rescue the spatial working memory and neuronal degeneration via reversal of mitochondrial dysfunction.	¹³
10	Apigenin decreases oxidative stress, levels of IL-6, TNF-α, mitochondrial-mediated neuron apoptosis and also downregulates TLR4/NF-kB signaling pathways in the acrylonitrile rat model of neuroinflammation. Results suggested that it could be a potent neuroprotective agent.	¹⁴
11	Apigenin rescues the behavioral impairments, cognitive deficits and increases the level of BDNF, cAMP, and CREB without altering seizure severity in pentylenetetrazole kindling associated behavioral and cognitive impairments in the mouse model. However, it also increases the serotonin level in the brain. The finding suggested that apigenin may be a potent therapeutic candidate to treat memory impairment and related diseases.	¹⁵
12	Apigenin shows a protective effect via detracting autophagy and apoptosis in the brain against ischemia/reperfusion injury. In-vivo results show apigenin significantly decreases neurobehavioral score and increases cell proliferation by the up-regulation of VEGFR22/CD3 and affecting caveolin-1, VEGF, eNOS expression in brain tissue of MCAO/R rats.	¹⁶
13	Apigenin promotes the upregulation of NF-kB gene expression and inhibits the release of pro-inflammatory cytokines IL-l, TNF-α, and also prevents the reduction of BDNF and GDNF levels in rotenone-induced rat model of PD. Thus, the results suggested that apigenin could serve as an effective agent for the management of PD.	¹⁷
14	Apigenin rescues the antioxidant machinery via the reduction of ROS levels, prevention of activation of stress kinase (IKKβ), JNK, and activation of NF-kB in high fat-high fructose diet induce rat model of hippocampal derangements. Results suggested that it has better antioxidant potential.	¹⁸
15	Apigenin recovers cognitive function via restoration of histone acetylation, BDNF signaling, and suppression of pro-inflammatory cytokines and NF-kB signaling pathway in an aged rat model of isoflurane-induced cognitive dysfunction. Thus, the study suggested that apigenin can be a potential drug candidate for the treatment of post-operational cognitive dysfunction.	¹⁹
16	Apigenin improves cognitive impairments in the rat model of post-stroke cognitive deficits, through decreased HDAC content, up-regulation H3 and H4 acetylation in the hippocampus and increased the level of BDNF in dose-dependent manner.	²⁰
17	Apigenin exhibits protective effect via reduction of MPO, ROS, MDA, and increases the level of oxidized glutathione (GSSG), GSH, hydrogen peroxide, and SOD in a rat model of SAH. Thus, the study suggested that apigenin may be considered as a potential drug for the management of SAH.	²¹
18	Apigenin exerts a neuroprotective effect against cerebral ischemic/reperfusion injury by promoting cell viability, cell proliferation and by reducing apoptotic cell death. The study revealed the neuroprotective effect of apigenin which is possibly induced by the STATE3 phosphorylation-mediated Mn-SOD up-regulation.	²²
19	Apigenin significantly increased retention of immune cells in the periphery and decreased expression of α4 integrin and CLEC12A on splenic dendritic cells in the autoimmune encephalomyelitis mice model. The study suggested that it could be a better treatment for the management of multiple sclerosis as compared to available treatment.	²³
20	Balez et al revealed that apigenin rescues the neurons from neuroinflammation, neuronal excitability, and apoptosis in the human induced pluripotent stem cell model of AD via the down-regulation of cytokines and nitric oxide release. These findings highlighted that apigenin could be a better therapeutic strategy for the management of AD.	²⁴
21	Apigenin mitigates neuroinflammation and astrocytes integrity by the downregulation of IL-6, IL-1β expression, and upregulation of IL-10 in LPS induce in vitro model of neuroinflammation associated with Alzheimer disease. Thus, the finding suggested that apigenin could be a potential agent for the treatment of neurodegenerative diseases.	²⁵
22	Apigenin shows a protective effect by the up-regulation of PPARγ expression, oxidative stress, inhibition of microglia, and NLRP3 activation, which subsequently down-regulate the production of IL-1β and IL-18 in a chronic unpredictable mild stress rat model of depression. Results suggested that it may be beneficial for the management of depression.	²⁶
23	Apigenin reverses the decreased level of Bcl-2 and Bid, loss of mitochondrial transmembrane potential, increase levels of Bax and p53, the release of Cytochrome c, activation of caspases (3, 8, and 9), and cleavage of PARP-1 in proteasome inhibitor induce neuronal apoptosis in both PC12 and SH-SY5Y cell lines.	²⁷
24	Apigenin significantly decreases early brain injury such as BBB disruption, brain edema, and cell apoptosis via the repression of NF-kB, TLR4, and their pro-inflammatory cytokines in the cortex in a rat model of subarachnoid hemorrhage. The finding suggested that apigenin could be protective against early brain injury.	²⁸
25	Apigenin elevates body weight, improves cognitive dysfunction, reduces blood glucose, MDA content, and increases SOD level in the cerebral cortex and hippocampus in the streptozotocin-induced rat model of diabetes-associated cognitive dysfunction. Finding suggested that apigenin could be an effective therapeutic agent for diabetes-associated cognitive decline in rats via the suppression of apoptotic, nitric oxide, and oxidative stress pathways.	²⁸
26	Apigenin rescues from the OGD/R induced neuron injury by the suppression of cell apoptosis, lactate dehydrogenase, and intracellular ROS level in PC12 cells. These results suggested that apigenin could be a therapeutic candidate against neuronal death.	²⁹
27	Apigenin and luteolin both in combination rescue the dopaminergic neurons through reducing microglial activation, neuroinflammation, oxidative stress as well as enhancement of BDNF in MPTP induced mice model of PD. The study suggested that both the molecules could be potential therapeutics in PD.	³⁰
28	Apigenin restores AD associated learning and memory impairment via the suppression of the amyloidogenic process, alleviating the Aβ burden, restoring ERK/CREB/BDNF pathway, and through prevention of oxidative stress in APP/PS1 double transgenic mouse model of AD. The finding suggested that apigenin could be an alternative agent for the prevention of AD-associated symptoms.	³¹
29	Apigenin exerts neuroprotective effect via maintaining redox balance by increasing cellular superoxide dismutase, glutathione level, and reduced ROS generation; obstructing p38 MAPK, MAPKAP kinase-2, heat shock protein 27 and c-jun N-terminal signaling pathways and reduced neuronal apoptosis in a copper-mediated β-amyloid neurotoxicity cell model of AD. The finding suggested that it could be a potential therapeutic for AD.	³²
30	Apigenin exhibits a protective effect via the up-regulation of SOD, GSH-Px activity, decrease serum level of IL-1β and TNF-α, and shows antioxidative, anti-inflammatory, and anti-apoptotic properties in modified weight-drop method induced rat model of spinal cord injury.	³³
31	Apigenin elicits neuroprotective effect through suppression of excitotoxicity in dose-dependent manner, ROS generation and reduction of GSH in hippocampal neurons in kainic acid induce an in vitro and in vivo model of excitotoxicity.	³⁴
32	Apigenin shows a neuro-protective effect in the Drosophila model of PD through increasing GSH, dopamine content, life span and reducing the level of GST activity, MAO, lipid peroxidation, and caspase 3/9 in a dose-dependent manner. The study highlighted the neuroprotective potential of apigenin in PD.	³⁵

Abbreviations:OGD/R, oxygen and glucose deprivation/reperfusion; ROS, reactive oxygen species; LPS, lipopolysaccharide; NF-κB, Nuclear factor kappa B; AP-SD, Solid dispersion of apigenin; SOD, superoxide dismutase; GSH, glutathione; MDA, malondialdehyde; AMD, age-related molecular degeneration; TNF, tumor necrosis factor; IL-6, interleukin-6; eNOS, endothelial nitric oxide synthase; MCAO/R, middle cerebral artery occlusion/reperfusion; IKKβ, Inhibitor of nuclear factor kappa-B kinase subunit beta; MPO, myeloperoxidase; SAH, subarachnoid hemorrhage; PD, Parkinson’s disease; AD, Alzheimer disease; GST, glutathione-S-transferase; MAO, monoamine oxidase.

Acknowledgments

The authors express their gratitude to Chairman, Mr. Praveen Garg and Director, Dr. G. D. Gupta, ISF College of Pharmacy Moga, Punjab, India for their excellent vision and support.

Ethical Issues

Not applicable.

Conflict of Interest

The authors declare that there is no conflict of interest.

References

The therapeutic potential of apigenin. Int J Mol Sci 2019; 20(6):1305. doi: 10.3390/ijms20061305 [Crossref]
Kumar A, Butt NA, Levenson AS. Natural epigenetic-modifying molecules in medical therapy. In: Tollefsbol TO, ed. Medical Epigenetics. Boston: Academic Press; 2016. p. 747-98. 10.1016/b978-0-12-803239-8.00039-9.
Plant flavone apigenin: an emerging anticancer agent. Curr Pharmacol Rep 2017; 3(6):423-46. doi: 10.1007/s40495-017-0113-2 [Crossref]
Apigenin: a promising molecule for cancer prevention. Pharm Res 2010; 27(6):962-78. doi: 10.1007/s11095-010-0089-7 [Crossref]
Apigenin as a candidate prenatal treatment for trisomy 21: effects in human amniocytes and the Ts1Cje mouse model. Am J Hum Genet 2020; 107(5):911-31. doi: 10.1016/j.ajhg.2020.10.001 [Crossref]
The neuroprotective effect of apigenin against OGD/R injury in rat hippocampal neurons. Pak J Pharm Sci 2020; 33(4):1527-33.
Efficiency comparison of apigenin-7-O-glucoside and trolox in antioxidative stress and anti-inflammatory properties. J Pharm Pharmacol 2020; 72(11):1645-56. doi: 10.1111/jphp.13347 [Crossref]
Apigenin protects mouse retina against oxidative damage by regulating the Nrf2 pathway and autophagy. Oxid Med Cell Longev 2020; 2020:9420704. doi: 10.1155/2020/9420704 [Crossref]
Luteolin and apigenin attenuate LPS-induced astrocyte activation and cytokine production by targeting MAPK, STAT3, and NF-κB signaling pathways. Inflammation 2020; 43(5):1716-28. doi: 10.1007/s10753-020-01245-6 [Crossref]
Apigenin-7-O-β-D-(-6”-p-coumaroyl)-glucopyranoside treatment elicits a neuroprotective effect through GSK-3β phosphorylation-mediated Nrf2 activation. Aging (Albany NY) 2020; 12(23):23872-88. doi: 10.18632/aging.104050 [Crossref]
The natural plant flavonoid apigenin is a strong antioxidant that effectively delays peripheral neurodegenerative processes. Anat Sci Int 2019; 94(4):285-94. doi: 10.1007/s12565-019-00486-2 [Crossref]
Evaluation of the neuroprotective, anticonvulsant, and cognition-improvement effects of apigenin in temporal lobe epilepsy: Involvement of the mitochondrial apoptotic pathway. Iran J Basic Med Sci 2019; 22(7):752-8. doi: 10.22038/ijbms.2019.33892.8064 [Crossref]
Protective role of apigenin against Aβ 25-35 toxicity via inhibition of mitochondrial cytochrome c release. Basic Clin Neurosci 2019; 10(6):557-66. doi: 10.32598/bcn.9.10.385 [Crossref]
Apigenin attenuates acrylonitrile-induced neuro-inflammation in rats: involved of inactivation of the TLR4/NF-κB signaling pathway. Int Immunopharmacol 2019; 75:105697. doi: 10.1016/j.intimp.2019.105697 [Crossref]
Apigenin reverses behavioural impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus. Nutr Neurosci 2020; 23(2):118-27. doi: 10.1080/1028415x.2018.1478653 [Crossref]
Apigenin protects the brain against ischemia/reperfusion injury via caveolin-1/VEGF in vitro and in vivo. Oxid Med Cell Longev 2018; 2018:7017204. doi: 10.1155/2018/7017204 [Crossref]
Protective role of apigenin on rotenone induced rat model of Parkinson’s disease: suppression of neuroinflammation and oxidative stress mediated apoptosis. Chem Biol Interact 2017; 269:67-79. doi: 10.1016/j.cbi.2017.03.016 [Crossref]
Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet. Biomed Pharmacother 2017; 89:323-31. doi: 10.1016/j.biopha.2017.01.162 [Crossref]
Apigenin attenuates isoflurane-induced cognitive dysfunction via epigenetic regulation and neuroinflammation in aged rats. Arch Gerontol Geriatr 2017; 73:29-36. doi: 10.1016/j.archger.2017.07.004 [Crossref]
Apigenin ameliorates post-stroke cognitive deficits in rats through histone acetylation-mediated neurochemical alterations. Med Sci Monit 2017; 23:4004-13. doi: 10.12659/msm.902770 [Crossref]
Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage. J Clin Neurosci 2017; 40:157-62. doi: 10.1016/j.jocn.2017.03.003 [Crossref]
Apigenin-7-O-β-D-(-6’’-p-coumaroyl)-glucopyranoside treatment elicits neuroprotective effect against experimental ischemic stroke. Int J Biol Sci 2016; 12(1):42-52. doi: 10.7150/ijbs.12275 [Crossref]
Apigenin, a natural flavonoid, attenuates EAE severity through the modulation of dendritic cell and other immune cell functions. J Neuroimmune Pharmacol 2016; 11(1):36-47. doi: 10.1007/s11481-015-9617-x [Crossref]
Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease. Sci Rep 2016; 6:31450. doi: 10.1038/srep31450 [Crossref]
Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain. Behav Brain Res 2016; 296:318-25. doi: 10.1016/j.bbr.2015.09.031 [Crossref]
Apigenin reduces proteasome inhibition-induced neuronal apoptosis by suppressing the cell death process. Neurochem Res 2016; 41(11):2969-80. doi: 10.1007/s11064-016-2017-7 [Crossref]
Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats. Int Immunopharmacol 2015; 28(1):79-87. doi: 10.1016/j.intimp.2015.05.024 [Crossref]
Apigenin attenuates diabetes-associated cognitive decline in rats via suppressing oxidative stress and nitric oxide synthase pathway. Int J Clin Exp Med 2015; 8(9):15506-13.
Apigenin mediated protection of OGD-evoked neuron-like injury in differentiated PC12 cells. Neurochem Res 2014; 39(11):2197-210. doi: 10.1007/s11064-014-1421-0 [Crossref]
RETRACTED: neuroprotective and neurotrophic effects of apigenin and luteolin in MPTP induced parkinsonism in mice. Neuropharmacology 2014; 86:192-202. doi: 10.1016/j.neuropharm.2014.07.012 [Crossref]
Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules 2013; 18(8):9949-65. doi: 10.3390/molecules18089949 [Crossref]
Apigenin attenuates copper-mediated β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res 2013; 1492:33-45. doi: 10.1016/j.brainres.2012.11.019 [Crossref]
Neuroprotective effect of apigenin in rats after contusive spinal cord injury. Neurol Sci 2014; 35(4):583-8. doi: 10.1007/s10072-013-1566-7 [Crossref]
Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol Pharm Bull 2012; 35(9):1440-6. doi: 10.1248/bpb.b110686 [Crossref]
Grape extract protects mitochondria from oxidative damage and improves locomotor dysfunction and extends lifespan in a Drosophila Parkinson’s disease model. Rejuvenation Res 2009; 12(5):321-31. doi: 10.1089/rej.2009.0877 [Crossref]