Molecular mechanisms of action Quisqualic acid is functionally similar to
glutamate, which is an endogenous agonist of glutamate's receptors. It functions as a neurotransmitter in insect neuromuscular junction and
CNS. It passes the blood brain barrier and binds to cell surface receptors
AMPA and
Kainate receptors in the brain. AMPA receptor is a type of ionotropic glutamate receptor coupled to ion channels and when bound to a ligand, it modulates the excitability by gating the flow of calcium and sodium ions into the intracellular domain. On the other hand, kainate receptors are less understood than AMPA receptors. Although, the function is somewhat similar: the ion channel permeates the flow of sodium and potassium ions, and to a lower extent the Calcium ions. As mentioned, binding of quisqualic acid to these receptors leads to an influx of calcium and sodium ions into the neurons, which triggers downstream signaling cascades. Calcium signaling involves protein effectors such as kinases (
CaMK,
MAPK/ERKs),
CREB-transcription factor and various phosphatases. It regulates gene expression and may modify the properties of the receptors. Sodium and calcium ions together generate an
excitatory postsynaptic potential (EPSP) that triggers
action potentials. It's worthwhile to mention that overactivation of glutamate receptors and kainate receptors lead to
excitotoxicity and
neurological damage. Metabotropic glutamate receptors, also known as
mGluRs are a type of glutamate receptor which are members of the
G-protein coupled receptors. These receptors are important in neural communication, memory formation, learning and regulation. Like Glutamate, quisqualic acid binds to this receptor and shows even a higher potency, mainly for mGlu1 and mGlu5 and exert its effects through a complex second messenger system. Activation of these receptors leads to an increase in
inositol triphosphate (IP3) and
diacylglycerol (DAG) by the activation of
phospholipase C (PLC). Eventually, IP3 diffuses to bind to IP3 receptors on the
ER, which are calcium channels that eventually increase the Calcium concentration in the cell.
Modulation of NMDA receptor The effects of quisqualic acid depend on the location and context. These 2 receptors are known to potentiate the activity of N-methyl-D-aspartate receptors (
NMDARs), a certain type of
ion channel that is a neurotoxic. Excessive amounts of NMDA have been found to cause harm to the neurons in the presence of mGlu1 and mGlu5 receptors.
Effects on plasticity Activation of group 1 mGluRs are implicated in
synaptic plasticity and contribute to both
neurotoxicity and
neuroprotection such as protection of the retina against NMDA toxicity, mentioned above. It causes a reduction in
ZENK expression, which leads to
myopia in chicken.
Role in disease Studies on mice have suggested that mGlu1 may be involved in the development of certain cancers. Knowing that these types of receptors are mostly localized in the
thalamus,
hypothalamus and
caudate nucleus regions of the brain, the overactivation of these receptors by quisqualic acid can suggest a potential role in movement disorders.
Use/purpose, availability, efficacy, side effects/ adverse effects Quisqualic acid is an excitatory amino acid (EAA) and a potent agonist of metabotropic glutamate receptors, where evidence shows that activation of these receptors may cause a long lasting sensitization of neurons to
depolarization, a phenomenon called the “Quis effect ”. Quisqualic acid has strong excitatory effects in the spinal cords of frogs and rats as well as on the
neuromuscular junction in crayfish. As template for excitotoxic models of
spinal cord injury, quisqualic acid can cause excessive activation of glutamate receptors, leading to neuronal damage and loss. This excitotoxic model has been used to study the mechanisms of injury and to develop potential treatments for related conditions. Several experimental studies have demonstrated the similarity between the pathology and symptoms induced by quisqualic acid injections and those observed in clinical spinal cord injuries. After administration of quis-injection, spinal neurons located close to areas of neuronal degeneration and cavitation exhibit a decrease in
mechanical threshold, meaning they become more sensitive to mechanical stimuli. This heightened sensitivity is accompanied by prolonged after discharge responses. These results suggest that excitatory amino acid agonists can induce morphological changes in the spinal cord, which can lead to physiological changes in adjacent neurons, ultimately resulting in altered mechanosensitivity. There is evidence to suggest that excitatory amino acids like quisqualic acid play a significant role in the induction of cell death following stroke, hypoxia-ischemia, and traumatic brain injury . Studies involving the binding of quisqualic acid have indicated that the amino acid does not show selectivity for a singular specific receptor subtype, which was initially identified as the quisqualate receptor. Regarding
bioavailability, no database information is present, as there is limited research on its
pharmacokinetics. However, even though the bioavailability is not well established, studies in rats suggest that age may play a role in the presence of administered quisqualic acid effects. An experiment which was done on rats within two age groups (20-days-old and 60-days-old) showed that, when given quisqualic acid microinjections, 60-day-old rats had more seizures compared to the younger rats. Additionally, the rats were given the same amount of quisqualic acid, however the immature animals received a higher dosage per body weight, implying that the harm inflicted by the excitatory amino acid may have been comparatively lower in the younger animals. == Metabolism/Biotransformation ==