Ibotenic acid or (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, also referred to as ibotenate, is a
chemical compound and
psychoactive drug which occurs naturally in Amanita muscaria and related species of
mushrooms typically found in the temperate and boreal regions of the northern hemisphere. It is a prodrug of
muscimol, broken down by the liver to that much more stable compound.[2] It is a conformationally-restricted
analogue of the
neurotransmitterglutamate, and due to its structural similarity to this neurotransmitter, acts as a non-selective
glutamate receptoragonist.[3] Because of this, ibotenic acid can be a powerful
neurotoxin in high doses, and is employed as a "brain-
lesioning agent" through cranial injections in
scientific research.[4][5] The neurotoxic effects appear to be dose-related and risks are unclear through consumption of ibotenic-acid containing fungi, although thought to be negligible in small doses.[6][better source needed]
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.[11]
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.
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.[12]
Biological effects
Ibotenic acid typically affects both NMDA and
APCD or
metabolotropic quisqualate receptor sites in the central nervous system.[11] 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.[13] 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.[14]
Symptoms are slightly different for children, typically beginning after 30–180 minutes. Dominant symptoms in children include
ataxia,
obtundation, and
lethargy. Seizures are occasionally reported, however, more commonly with children.[14]
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.[15]
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.[16]
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 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.[17]
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.[18]
^Jarrard, Leonard (2 February 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.