Ibotenic acid or (''S'')-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, also referred to as ibotenate, is a naturally occurring alpha-amino acid found in certain ''

Amanita The genus ''Amanita'' contains about 600 species of agarics, including some of the most toxic known mushrooms found worldwide, as well as some well-regarded Edible mushroom, edible species (and many species of unknown edibility). The genus is re ...

'' mushrooms, that primarily acts as a potent glutamate receptor agonist that precipitates neurological effects and is used experimentally as a brain-lesioning agent in mice and rats. Ibotenic acid is a conformationally-restricted analogue of

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

that acts as a non-selective

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

agonist, strongly activating NMDA, group I and II metabotropic glutamate receptors, and weakly activating

AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate Glutamic acid (symbol Glu or E; kn ...

and kainate receptors. It is a prodrug of muscimol, broken down by the liver into this more stable compound, which acts as a potent GABA_A and GABA_A-ρ receptor agonist. Although its psychoactive effects are not well understood, some researchers speculate that ibotenic acid itself may have

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

properties. Ibotenic acid is biosynthesized from glutamic acid by hydroxylation catalyzed by an Fe(II)/2- oxoglutarate-dependent oxygenase, with subsequent conversion steps carried out by enzymes encoded within a linked biosynthetic

gene cluster A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...

. Ibotenic acid is commonly used in research to create site-specific hippocampal brain lesions in rats, allowing for task relearning due to its interaction with glutamate receptors, and is favored over other agents for its selectivity and long-term stability in saline solution. It induces excitotoxicity in mice and rats by overactivating NMDA and metabotropic glutamate receptors, leading to calcium overload and oxidative damage. In contrast, it targets glutamate-gated chloride channels in

invertebrates Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordate subphylum ...

, causing increased chloride permeability without affecting their excitatory glutamate receptors.

Pharmacology

Ibotenic acid acts as a potent

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the NMDA and group I ( mGluR1 and mGluR5) and II ( mGluR2 and mGluR3) metabotropic glutamate receptors. It is inactive at group III mGluRs. Ibotenic acid also acts as a weak agonist of the

and kainate receptors. In addition, due to ''in vivo'' decarboxylation into muscimol, it acts indirectly as a potent GABA_A and GABA_A-ρ receptor agonist. Unlike muscimol—the principal psychoactive constituent of ''Amanita muscaria'' that is understood to cause sedation and delirium—ibotenic acid's psychoactive effects are not known independent of its serving as a prodrug to muscimol, although some researchers have speculated that it would act as a stimulant.

Biological properties

Mechanism of action

Ibotenic acid is an

of glutamate receptors, specifically at both the N-methyl-D-aspartate, or NMDA, and trans-ACPD receptor sites in multiple systems in 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 ...

. Ibotenic neurotoxicity can be enhanced by glycine and blocked by dizocilpine. Dizocilpine acts as an uncompetitive antagonist at

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

s. Ibotenic acid toxicity comes from activation of the NMDA receptors. NMDA receptors are related to

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

and work with metabotropic glutamate receptors to establish long term potentiation or LTP. The process of long term potentiation is believed to be related to the acquisition of information. The NMDA receptor functions properly by allowing Ca²⁺ ions to pass through after activation at the receptor site. Activated NMDAR

The binding of ibotenic acid allows excess Ca²⁺ into the system which results in neuronal cell death. Ca²⁺ also activates CaM-KII or Ca²⁺/Calmodulin Kinase which phosphorylates multiple enzymes. The activated enzymes then begin producing reactive oxygen species which damages surrounding tissue. The excess Ca²⁺ results in the enhancement of the mitochondrial electron transport system which will further increase the number of reactive oxygen species.

Biological effects

Ibotenic acid typically affects both NMDA and APCD or metabolotropic quisqualate receptor sites in the central nervous system. Due to their targeting of these systems the symptoms associated with ibotenic acid poisoning are often related to perception and control. At least some ingested ibotenic acid is likely decarboxylated into muscimol so some of the effects of ingesting ibotenic acid are similar to muscimol's effects. Symptoms associated with ibotenic acid are usually onset within 30–60 minutes and include a range of nervous system effects. The most common symptoms include nausea, vomiting, and drowsiness. However, after the first hour symptoms begin to include confusion, euphoria, visual and auditory distortions, sensations of floating, and retrograde amnesia. Symptoms are slightly different for children, typically beginning after 30–180 minutes. Dominant symptoms in children include

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, obtundation, and lethargy. Seizures are occasionally reported, however, more commonly with children. In contrast, ibotenic acid has a completely different action in invertebrates. Instead of an excitatory effect, it increases the permeability of invertebrate skeletal muscle and nerve cell membranes to chloride ions but shows no affinity for invertebrate

excitatory receptors. This effect was first observed in locust muscle fibers, leading to the discovery of a new ion channel, the glutamate-gated chloride channel (GluCl), which was later cloned from the soil nematode C. elegans.Similar effects have been observed in other invertebrate excitable cells, including Drosophila melanogaster neurons and crayfish muscle. Since GluCl does not exist in vertebrates, it has become a valuable target for anti-parasitic drugs such as Avermectin and Ivermectin.

Treatment

Treatment of ibotenic acid toxicity centres around supportive care and treatment of symptoms; no antidote is available. Gastric decontamination with activated charcoal or gastric lavage can be of benefit if the patient presents early. The psychotropic effects and hallucinations ibotenic acid and its metabolite muscimol produce are best managed in a quiet environment with minimal stimulation.

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 ...

s can be of benefit in agitated or panicked patients; they can also be used to control seizures if they occur. Benzodiazepines as a GABA-A PAM interacts with Muscimol as a GABA-A agonist and may cause a significantly increased risk of depressant effects.

Airway management Airway management includes a set of maneuvers and medical procedures performed to prevent and relieve an airway obstruction. This ensures an open pathway for gas exchange between a patient's lungs and the atmosphere. This is accomplished by either ...

may be required if sedation is profound. Symptoms usually resolve within a few hours of ingestion but can last for days following significant exposures. Monitoring for the presence of brain lesions may be required following a large or repeated exposure. Other measures may be required if the patient has been exposed to a mushroom such as ''

Amanita muscaria ''Amanita muscaria'', commonly known as the fly agaric or fly amanita, is a basidiomycete fungus of the genus ''Amanita''. It is a large white-lamella (mycology), gilled, white-spotted mushroom typically featuring a bright red cap covered with ...

'' as other active compounds may be present.

Use in research

Ibotenic acid used for the lesioning of rat's brains is kept frozen in a phosphate-buffered Saline Solution at a pH of 7.4, and can be kept for up to a year with no loss in toxicity. Injection of .05-.1 microliters of Ibotenic acid into the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

at a rate of .1 microliter/min resulted in semi-selective lesioning. Hippocampal lesioning led to a considerable loss of cells in pyramidal cells (CA1-CA3) as well as granule cells in the dentate gyrus. Ibotenic acid lesioning also causes some damage to axons along the perforant pathway. Typically, when lesioning is done with other chemicals the subject cannot relearn a task. However, due to Ibotenic acid's reactivity with glutamate receptors such as the NMDA receptor, Ibotenic acid lesioning does allow the subject to relearn tasks. Ibotenic acid lesioning is thus preferred in studies where re-learning a task after lesioning is essential. Compared to other lesioning agents, Ibotenic acid is one of the most site-specific; however, less-damaging alternatives are presently sought.

Biosynthesis

Ibotenic acid's biosynthetic genes are organized in a physically linked biosynthetic gene cluster. The biosynthetic pathway is initiated by hydroxylation of

glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...

by a dedicated Fe(II)/2-oxoglutarate-dependent oxygenase. The reaction yields ''threo''-3-hydroxyglutamic acid, which is converted into ibotenic acid, likely by enzymes encoded in the biosynthetic gene cluster.

References

{{Authority control Toxic amino acids Neurotoxins Mycotoxins found in Basidiomycota Prodrugs Isoxazoles Hydroxy acids AMPA receptor agonists GABAA receptor agonists GABAA-rho receptor agonists Kainate receptor agonists MGlu1 receptor agonists MGlu2 receptor agonists MGlu3 receptor agonists MGlu5 receptor agonists NMDA receptor agonists Excitotoxins Hydroxyarenes Hallucinogens