Ibotenic acid - WikiHQ

Ibotenic acid, or ibotenate, also known as premuscimol or as (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, is a naturally occurring α-amino acid found in certain Amanita mushrooms such as Amanita muscaria. It acts primarily as a potent glutamate receptor agonist and produces neurological effects.

Ibotenic acid is a conformationally-restricted analogue of the excitatory neurotransmitter glutamate which acts as a non-selective agonist of glutamate receptors, strongly activating NMDA, group I and II metabotropic glutamate receptors, and weakly activating AMPA and kainate receptors. Taken systemically, it is a prodrug of muscimol, broken down by the liver into this more stable compound, which acts as a potent GABAA and GABAA-ρ receptor agonist. Although the compound's psychoactive effects are not well-understood, some researchers speculate that ibotenic acid itself may have stimulant-like 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.

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 rodents by overactivating NMDA and metabotropic glutamate receptors, leading to calcium overload and oxidative damage. In contrast, it targets glutamate-gated chloride channels in invertebrates, causing increased chloride permeability without affecting their excitatory glutamate receptors. It is active at doses of approximately 20 to 100mg orally in humans. The onset of ibotenic acid is slow, with full effects developing after 2 to 3hours, while the duration is 6 to 8hours. It is inactive at group III mGluRs. Ibotenic acid also acts as a weak agonist of the AMPA and kainate receptors.

Ibotenic acid is an agonist 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. Ibotenic neurotoxicity can be enhanced by glycine and blocked by dizocilpine. Dizocilpine acts as an uncompetitive antagonist at NMDA receptors.

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

class=skin-invert-image|thumb|right|upright|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.

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 glutamate 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. Benzodiazepines 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 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 as other active compounds may be present.

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 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.

History

The neurotoxic (brain-damaging) effects of ibotenic acid were first described by 1979.

Ibotenic acid was found to be sold online in 2023.

References

External links

Ibotenic acid - Isomer Design
Ibotenic acid - PsychonautWiki
Amanita muscaria - PsychonautWiki
Psychoactive Amanitas - Erowid
r/AmanitaMuscaria - Reddit