Contents lists available at ScienceDirect Phytomedicine journal homepage: www.elsevier.com/locate/phymed Pharmacology and toxicology of α- and β-Asarone: A review of preclinical evidence Ranjithkumar Chellian, Vijayapandi Pandy*, Zahurin Mohamed Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia ARTICLE INFO Keywords: Pharmacokinetics Pharmacology Toxicology α-Asarone β -Asarone ABSTRACT Background: Asarone is one of the most researched phytochemicals and is mainly present in the Acorus species and Guatteria gaumeri Greenman. In preclinical studies, both α- and β-asarone have been reported to have nu- merous pharmacological activities and at the same time, many studies have also revealed the toxicity of α- and β- asarone. Purpose: The purpose of this comprehensive review is to compile and analyze the information related to the pharmacokinetic, pharmacological, and toxicological studies reported on α- and β-asarone using preclinical in vitro and in vivo models. Besides, the molecular targets and mechanism(s) involved in the biological activities of α- and β-asarone were discussed. Methods: Databases including PubMed, ScienceDirect and Google scholar were searched and the literature from the year 1960 to January 2017 was retrieved using keywords such as α-asarone, β-asarone, pharmacokinetics, toxicology, pharmacological activities (e.g. depression, anxiety). Results: Based on the data obtained from the literature search, the pharmacokinetic studies of α- and β-asarone revealed that their oral bioavailability in rodents is poor with a short plasma half-life. Moreover, the metabolism of α- and β-asarone occurs mainly through cytochrome-P450 pathways. Besides, both α- and/or β-asarone possess a wide range of pharmacological activities such as antidepressant, antianxiety, anti-Alzheimer's, anti- Parkinson's, antiepileptic, anticancer, antihyperlipidemic, antithrombotic, anticholestatic and radioprotective activities through its interaction with multiple molecular targets. Importantly, the toxicological studies revealed that both α- and β-asarone can cause hepatomas and might possess mutagenicity, genotoxicity, and ter- atogenicity. Conclusions: Taken together, further preclinical studies are required to confirm the pharmacological properties of α-asarone against depression, anxiety, Parkinson's disease, psychosis, drug dependence, pain, inflammation, cholestasis and thrombosis. Besides, the anticancer effect of β-asarone should be further studied in different types of cancers using in vivo models. Moreover, further dose-dependent in vivo studies are required to confirm the toxicity of α- and β-asarone. Overall, this extensive review provides a detailed information on the preclinical pharmacological and toxicological activities of α-and β-asarone and this could be very useful for researchers who wish to conduct further preclinical studies using α- and β-asarone. Introduction The plant from the Acorus species, Acorus calamus Linn (Acoraceae), commonly known as “sweet flag”, has been widely used alone or in combination with other herbs in traditional Indian and Chinese medicine over centuries (Rajput et al., 2014). The other Acorus species such as Acorus tatarinowii Schott (Acoraceae) and Acorus gramineus Solander (Acoraceae) are renowned indigenous Chinese medicinal plants, officially listed in the Chinese Pharmaco- poeia (Huang et al., 2013; Wang et al., 2014). The Acorus species are http://dx.doi.org/10.1016/j.phymed.2017.04.003 Received 11 November 2016; Received in revised form 20 March 2017; Accepted 8 April 2017 * Corresponding author. E-mail addresses: pandiphd@gmail.com, pandiphd@um.edu.my (V. Pandy). Abbreviations: Aβ, β-amyloid peptides; AChE, Acetylcholinesterase; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; Bcl, B-cell lymphoma; b.i.d, twice daily; CNS, central nervous system; CYP450, cytochrome P450; CREB, cAMP response element-binding protein; cDNA, complementary DNA; DNA, Deoxyribonucleic acid; EAAC1, excitatory amino acid carrier 1; EPM, elevated plus maze; GABA, gamma-amino butyric acid; HMGCR, 3- hydroxyl-3-methyl-glutaryl-coenzyme A reductase; HFD, high-fat diet; HDL, high-density lipoprotein; IL, interleukin; i.p., intraperitoneal route; i.v., intravenous route; JNK, c-jun N-terminal kinases; LC, light chain; LDL, low- density lipoprotein; LPS, lipopolysaccharide; MAO, monoamine oxidase; MMP, matrix metalloproteinase; MDR, multiple drug resistance; NMDA, N-methyl-D-aspartate; o.d., once daily; p.o., oral route; s.c., subcutaneous route; SAMP-8, senescence accelerated mouse-prone 8 mice; TST, tail suspension test; 5-HT, 5-hydroxytryptamine; 6-OHDA, 6-hydroxydopamine Phytomedicine 32 (2017) 41–58 0944-7113/ © 2017 Elsevier GmbH. All rights reserved. MARK