Ibotenic acid is commonly used in research to create site-specifichippocampalbrain 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 insaline solution.[6][7] It inducesexcitotoxicity in rodents by overactivating NMDA and metabotropic glutamate receptors, leading to calcium overload andoxidative damage. In contrast, it targets glutamate-gatedchloride channels ininvertebrates, causing increased chloride permeability without affecting their excitatory glutamate receptors.[8][9]
Ibotenic acid is anagonist of glutamate receptors, specifically at both the N-methyl-D-aspartate, orNMDA, and trans-ACPD receptor sites in multiple systems in thecentral nervous system. Ibotenic neurotoxicity can be enhanced by glycine and blocked bydizocilpine.Dizocilpine acts as an uncompetitive antagonist atNMDA receptors.[16]
Ibotenic acid toxicity comes from activation of theNMDA receptors. NMDA receptors are related tosynaptic plasticity and work withmetabotropic glutamate receptors to establishlong 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 activatesCaM-KII or Ca2+/Calmodulin Kinase which phosphorylates multiple enzymes. The activated enzymes then begin producingreactive 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.[17]
Ibotenic acid typically affects both NMDA andAPCD ormetabolotropic quisqualate receptor sites in the central nervous system.[16] 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 likelydecarboxylated intomuscimol so some of the effects of ingesting ibotenic acid are similar to muscimol's effects.[1] 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 andauditory distortions, sensations of floating, andretrograde amnesia.[18]
Symptoms are slightly different for children, typically beginning after 30–180 minutes. Dominant symptoms in children includeataxia,obtundation, andlethargy. Seizures are occasionally reported, however, more commonly with children.[18]
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 nervecell membranes to chloride ions but shows no affinity for invertebrateglutamate excitatory receptors. This effect was first observed in locust muscle fibers,[8][9][19] leading to the discovery of a new ion channel, the glutamate-gated chloride channel (GluCl), which was later cloned from thesoil nematode C. elegans.[20]Similar effects have been observed in other invertebrate excitable cells, including Drosophila melanogaster neurons and crayfish muscle.[21][22]
Since GluCl does not exist in vertebrates, it has become a valuable target foranti-parasitic drugs such as Avermectin and Ivermectin.[21][22][23]
Treatment of ibotenic acid toxicity centres around supportive care and treatment of symptoms; no antidote is available. Gastric decontamination withactivated charcoal orgastric lavage can be of benefit if the patient presents early. The psychotropic effects and hallucinations ibotenic acid and its metabolitemuscimol 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.[24]
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 asAmanita muscaria as other active compounds may be present.[1]
Ibotenic acid used for the lesioning of rat's brains is kept frozen in a phosphate-bufferedSaline 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 thehippocampus at a rate of .1 microliter/min resulted in semi-selective lesioning. Hippocampal lesioning led to a considerable loss of cells inpyramidal cells (CA1-CA3) as well asgranule cells in thedentate gyrus. Ibotenic acid lesioning also causes some damage to axons along theperforant 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.[25]
^abStebelska K (August 2013). "Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities".Therapeutic Drug Monitoring.35 (4):420–442.doi:10.1097/FTD.0b013e31828741a5.PMID23851905.
^abOkhovat A, Cruces W, Docampo-Palacios ML, Ray KP, Ramirez GA (2023). "Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties".International Journal of Medicinal Mushrooms.25 (9):1–10.doi:10.1615/IntJMedMushrooms.2023049458.PMID37824402.
^abKrogsgaard-Larsen P, Hansen JJ (December 1992). "Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design".Toxicology Letters. 64-65 Spec No:409–416.doi:10.1016/0378-4274(92)90214-5.PMID1335179.
^Becker A, Grecksch G, Bernstein HG, Höllt V, Bogerts B (June 1999). "Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis".Psychopharmacology.144 (4):333–338.doi:10.1007/s002130051015.PMID10435405.S2CID25172395.
^abLea TJ, Usherwood PN (December 1973). "The site of action of ibotenic acid and the identification of two populations of glutamate receptors on insect muscle-fibres".Comparative and General Pharmacology.4 (16):333–350.doi:10.1016/0010-4035(73)90045-1.PMID4799403.
^abLea TJ, Usherwood PN (December 1973). "Effect of ibotenic acid on chloride permeability of insect muscle-fibres".Comparative and General Pharmacology.4 (16):351–363.doi:10.1016/0010-4035(73)90046-3.PMID4799404.
^Hermit MB, Greenwood JR, Nielsen B, Bunch L, Jørgensen CG, Vestergaard HT, et al. (February 2004). "Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors".European Journal of Pharmacology.486 (3):241–250.doi:10.1016/j.ejphar.2003.12.033.PMID14985045.
^Theobald W, Büch O, Kunz HA, Krupp P, Stenger EG, Heimann H (March 1968). "[Pharmacological and experimental psychological studies with 2 components of fly agaric (Amanita muscaria)]".Arzneimittel-Forschung (in German).18 (3):311–5.PMID5696006.
^Chilton WS, Ott J (1976). "Toxic metabolites of Amanita pantherina, A. cothurnata, A. muscaria and other Amanita species".Lloydia.39 (2–3):150–7.PMID985999.
^abZinkand WC, Moore WC, Thompson C, Salama AI, Patel J (February 1992). "Ibotenic acid mediates neurotoxicity and phosphoinositide hydrolysis by independent receptor mechanisms".Molecular and Chemical Neuropathology.16 (1–2):1–10.doi:10.1007/bf03159956.PMID1325800.
^Cull-Candy SG, Usherwood PN (November 1973). "Two populations of L-glutamate receptors on locust muscle fibres".Nature.246 (150):62–64.doi:10.1038/newbio246062a0.PMID4519031.
^Cully DF, Vassilatis DK, Liu KK, Paress PS, Van der Ploeg LH, Schaeffer JM, et al. (October 1994). "Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans".Nature.371 (6499):707–711.Bibcode:1994Natur.371..707C.doi:10.1038/371707a0.PMID7935817.
^abZufall F, Franke CH, Hatt H (March 1989). "The insecticide avermectin b (la) activates a chloride channel in crayfish muscle membrane".The Journal of Experimental Biology.142 (1):191–205.Bibcode:1989JExpB.142..191Z.doi:10.1242/jeb.142.1.191.PMID22135837.
^Jarrard LE (September 1989). "On the use of ibotenic acid to lesion selectively different components of the hippocampal formation".Journal of Neuroscience Methods.29 (3):251–259.doi:10.1016/0165-0270(89)90149-0.PMID2477650.S2CID3767525.
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