Иботеновая кислота: нейротоксичность, действие и симптомы отравления.

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. It is a conformationally restricted analogue of the neurotransmitter glutamate, and due to its structural similarity to this neurotransmitter, acts as a non selective glutamate receptor agonist. 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. 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.

Ibotenic acid acts as a potent agonist 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 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. 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.

Ibotenic acid typically affects both NMDA and APCD or metabolotropic quisqualate receptor sites in the central nervous system. 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.

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.

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.

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.