Kynurenic acid ( KYNA or KYN ) is a product of the normal metabolism of amino acid L - tryptophan . It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant , most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.
20-405: AP5 (also known as APV , (2 R )-amino-5-phosphonovaleric acid , or (2 R )-amino-5-phosphonopentanoate ) is a chemical compound used as a biochemical tool to study various cellular processes. It is a selective NMDA receptor antagonist that competitively inhibits the ligand (glutamate) binding site of NMDA receptors . AP5 blocks NMDA receptors in micromolar concentrations (~50 μM). AP5 blocks
40-541: A clinical setting. In 2019, esketamine , an NMDA antagonist enantiomer of ketamine, was approved for use as an antidepressant in the United States. In 2022, Auvelity was approved by the FDA for the treatment of depression. This combination medication contains dextromethorphan , an NMDA receptor antagonist. Olney's lesions involve mass vacuolization of neurons observed in rodents. However, many suggest that this
60-720: A site within the ion channel. These drugs act at the glycine binding site: Kynurenic acid Kynurenic acid was discovered in 1853 by the German chemist Justus von Liebig in dog urine , which it was apparently named after. It is formed from L - kynurenine in a reaction catalyzed by the enzyme kynurenine—oxoglutarate transaminase . KYNA has been proposed to act on five targets: High levels of kynurenic acid have been identified in patients with tick-borne encephalitis , schizophrenia and HIV -related illnesses. In all these situations, increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in
80-411: A state called dissociative anesthesia , marked by catalepsy , amnesia , and analgesia . Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics. Dextrorphan , a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world ),
100-556: Is implicated in excitotoxicity , NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal, traumatic brain injury , stroke , and neurodegenerative diseases such as Alzheimer's , Parkinson's , and Huntington's . This is counterbalanced by the risk of developing Olney's lesions , and studies have started to find agents that prevent this neurotoxicity. Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of
120-470: Is known to be an NMDA receptor antagonist. Numerous detrimental symptoms are linked to depressed NMDA receptor function. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging . Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia ). Increased levels of another NMDA antagonist, kynurenic acid , may aggravate
140-622: Is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity . A 2009 review found no evidence of ketamine-induced neuron death in humans. However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not. Many drugs have been found that lessen
160-414: The brain as a glycine -site NMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in the pathophysiology and pathogenesis of schizophrenia. The kynurenic acid hypothesis of schizophrenia was proposed in 2007, based on its action on midbrain dopamine activity and NMDArs, thus linking dopamine hypothesis of schizophrenia with the glutamate hypothesis of
180-650: The brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated." Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists block binding to neurotransmitter glutamate sites; glycine antagonists block binding to glycine sites; noncompetitive antagonists inhibit binding to NMDARs allosteric sites; and uncompetitive antagonists block binding to
200-427: The brain, i.e., AMPA and kainate receptors . AP5 can block the conversion of a silent synapse to an active one, since this conversion is NMDA receptor-dependent. NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize , or inhibit the action of, the N -Methyl- D -aspartate receptor ( NMDAR ). They are commonly used as anesthetics for humans and animals;
220-478: The brains of mice, their cognition was shown to improve markedly. However, kynurenic acid also shows neuroprotective properties. Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells. Elevated levels of kynurenic acid compared to kynurenine appear to be associated with poorer T cell response and higher mortality in male subjects with COVID-19 , suggesting an explanation for
SECTION 10
#1732790537582240-410: The cellular analog of classical conditioning in the sea slug Aplysia californica , and has similar effects on Aplysia long-term potentiation (LTP), since NMDA receptors are required for both. It is sometimes used in conjunction with the calcium chelator BAPTA to determine whether NMDARs are required for a particular cellular process. AP5/APV has also been used to study NMDAR-dependent LTP in
260-420: The disease. Kynurenic acid is reduced in individuals with mood disorders, such as major depressive disorder and bipolar disorder , especially during depressive episodes. High levels of kynurenic acid have been identified in human urine in certain metabolic disorders, such as marked pyridoxine deficiency and deficiency/absence of kynureninase . When researchers decreased the levels of kynurenic acid in
280-433: The drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however. Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal. The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in
300-404: The mammalian hippocampus. In general, AP5 is very fast-acting within in vitro preparations, and can block NMDA receptor action at a reasonably small concentration. The active isomer of AP5 is considered to be the D configuration, although many preparations are available as a racemic mixture of D - and L -isomers. It is useful to isolate the action of other glutamate receptors in
320-417: The poorer clinical outcomes observed in males than in females. One controlled study kept mice on a ketogenic diet and measured kynurenic acid concentrations in different parts of the brain. It found that the mice on the ketogenic diet had greater kynurenic acid concentrations in the striatum and hippocampus compared to mice on a normal diet, with no significant difference in the cortex. In response to
340-495: The risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics , diazepam , barbiturates , ethanol , 5-HT 2A serotonin receptor agonists , anticonvulsants , and muscimol . Since NMDA receptor overactivation
360-635: The state of anesthesia they induce is referred to as dissociative anesthesia. Several synthetic opioids function additionally as NMDAR-antagonists, such as pethidine , levorphanol , methadone , dextropropoxyphene , tramadol , and ketobemidone . Some NMDA receptor antagonists, such as ketamine , dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N 2 O), are sometimes used as recreational drugs , for their dissociative, hallucinogenic , and euphoriant properties. When used recreationally, they are classified as dissociative drugs . NMDA receptor antagonists induce
380-468: The strength thereof vary from drug to drug. Most NMDA receptor antagonists are metabolized in the liver . Frequent administration of most NMDA receptor antagonists can lead to tolerance , whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream. NMDA receptor antagonists are also under investigation as antidepressants. Ketamine has been demonstrated to produce lasting antidepressant effects after administration in
400-811: The symptoms of schizophrenia, according to the "kynurenic hypothesis". NMDA receptor antagonists can mimic these problems; they sometimes induce " psychotomimetic " side effects, symptoms resembling psychosis . Such side effects caused by NMDA receptor inhibitors include hallucinations , paranoid delusions , confusion , difficulty concentrating , agitation , alterations in mood , nightmares , catatonia , ataxia , anesthesia , and learning and memory deficits. Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine , ketamine , and dextromethorphan , are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and
#581418