Kavain is the principal

kavalactone Kavalactones are a class of lactone compounds found in kava roots and ''Alpinia zerumbet'' (shell ginger) and in several Gymnopilus, Phellinus and Inonotus fungi. Some kavalactones are bioactive. They are responsible for the psychoactive, analges ...

found in the roots of the kava plant ('' Piper methysticum''), where it contributes significantly to the plant’s psychoactive and anxiolytic effects. Kavain exhibits anticonvulsant properties by modulating voltage-dependent sodium and calcium channels, and it may influence mood and anxiety through reversible inhibition of

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

and monoamine oxidase B, potentially affecting

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

signaling. Although it does not bind to the

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

site of

GABAA receptor The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous Ligand (biochemistry), ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regul ...

s, kavain potentiates GABA activity at extrasynaptic α4β2δ GABAA receptors and overlaps with the modulatory pathways of certain

general anesthetic General anaesthetics (or anesthetics) are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of aware ...

s. It also shows weak sodium antagonism, strong L-type calcium channel blockade, and enhances early potassium currents, suggesting mood-stabilizing effects akin to lamotrigine. Its precise mechanisms remain under investigation, but its activity across multiple pathways makes it a promising candidate for drug development targeting ion channels,

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

, and

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...

enzymes.

Pharmacology

Kavain has

anticonvulsive Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epilepsy, epileptic seizures. Anticonvulsants are also used in the ...

properties, attenuating

vascular Vascular can refer to: * blood vessels, the vascular system in animals * vascular tissue Vascular tissue is a complex transporting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue ...

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

contraction through interactions with voltage-dependent and channels. How this effect is mediated, and to what extent this mechanism is involved in the

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

and

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects of kavalactones on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, is unknown. The recent finding that kavain can reversibly inhibit both

and monoamine oxidase B suggests that kavain may exert some of its effects by modulating

, and

signaling. However, the precise mechanisms underlying the

psychotropic A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

, and

actions of kavain and related kavalactones are still debated. Direct binding to the

flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

of the

GABA-A receptor The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic tra ...

does not occur with kavain

enantiomers In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

. Many studies involved kava extracts from different plant parts and are, therefore, not applicable to kavain itself. Kavain directly modulates several human GABA_A receptor subtypes—most strongly α4β2δ—via a mechanism independent of the classical benzodiazepine binding site; its reduced efficacy at receptors carrying the β3N265M anesthetic-resistance mutation suggests overlap with the modulatory pathways of certain

s. A comparative review of

in-vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

studies with kavain (and related kavapyrones) to commonly used

antiepileptic Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatmen ...

drugs and

mood stabilizer A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, such as bipolar disorder and the bipolar type of schizoaffective disorder. Uses Mood stabilizers are best known for t ...

s affecting ion fluxes indicates that the kavapyrones are weakly Na+ antagonistic and therefore antiepileptic. They also have pronounced L- type channel antagonistic properties and act as a positive modulator of the early K+ outward current, which contribute to mood stabilizing properties similar to lamotrigine. Kavain and analogs remain interesting for

drug discovery In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or ...

against a variety of cellular targets, including

(Pgp),

, and

cyclo-oxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as pr ...

(COX) enzymes among others.

References

{{GABAAR PAMs Kavalactones Ethers Alkene derivatives Sedatives Anxiolytics GABAA receptor positive allosteric modulators Norepinephrine reuptake inhibitors Calcium channel blockers Sodium channel blockers Monoamine oxidase inhibitors

Pharmacology

See also

References