Kainic acid

Kainic acid is commonly injected into laboratory animal models to study the effects of experimental ablation. Kainic acid is a direct agonist of the glutamic kainate receptors and large doses of concentrated solutions produce immediate neuronal death by overstimulating neurons to death. Such damage and death of neurons is referred to as an excitotoxic lesion. Thus, in large, concentrated doses kainic acid can be considered a neurotoxin, and in small doses of dilute solution kainic acid will chemically stimulate neurons. In fact, kainate seems to regulate serotonergic activity in the vertebrate retina.

Electrical stimulation of designated areas of the brain are generally administered by passing an electric current through a wire that is inserted into the brain to lesion a particular area of the brain. Electrical stimulation indiscriminately destroys anything in the vicinity of the electrode tip, including neural bodies and axons of neurons passing through; therefore it is difficult to attribute the effects of the lesion to a single area. Chemical stimulation is typically administered through a cannula that is inserted into the brain via stereotactic surgery. Chemical stimulation, while more complicated than electrical stimulation, has the distinct advantage of activating cell bodies, but not nearby axons, because only cell bodies and subsequent dendrites contain glutamate receptors. Therefore, chemical stimulation by kainic acid is more localized than electrical stimulation. Both chemical and electrical lesions potentially cause additional damage to the brain due to the very nature of the inserted electrode or cannula. Therefore, the most effective ablation studies are performed in comparison to a sham lesion that duplicates all the steps of producing a brain lesion except the one that actually causes the brain damage, that is, injection of kainic acid or administration of an electrical shock.

Biosynthesis

In 2019, Chekan et al. were able to use bioinformatic tools to look for domoic acid gene homologs in the seaweed Digenea simplex. Researchers identified a cluster containing genes identified as the kainic acid biosynthesis (kab) genes. This cluster contains an annotated N-prenyltransferase, α-ketoglutarate (αKG)-dependent dioxygenase, and several retrotransposable elements. To confirm production of kainic acid through the identified cluster, Chekan et al. expressed the genes in Escherichia coli and validated the enzymatic functions of each proposed gene.

The first step of the pathway involves the N-prenyltransferase, KabA, which allows for the prenylation of L-glutamic acid with dimethylallyl pyrophosphate (DMAPP) to form the intermediate N-dimethylallyl-l-glutamic acid (prekainic acid). KabC then catalyzes the stereocontrolled formation of the trisubstituted pyrrolidine ring, taking prekainic acid to the final kainic acid. KabC was also able to produce another kainic acid isomer, kainic acid lactone.