Kainic Acid

Kainic acid is an amino acid that is involved in binding to and activating kainate receptors – a type of glutamate receptors found on neurons and the role of kainate receptors in neurotoxicity is not clear.[1]. Kainic acid causes changes that the central nervous system will undergo.[2]. When kainic acid binds to kainate receptors, it causes many incidents such as an increase in intracellular calcium, producing reactive oxygen species, and mitochondrial dysfunction. [2]. In an experiment with rodents, the following results have been demonstrated: kianic acid causes behavioral changes and recurrent seizures, selective hippocampal degeneration, activation of glial, and it also increases inflammatory mediators in the CNS.[2].

As mentioned earlier, kianic acid can cause behavioral changes and seizures. In a rats study, it has shown that the most common changes in behavior were strong immobility known as catatonia, ‘wet dog shake’, and generalized tonic-clonic convulsions. [3]. These behavioral changes had a rapid onset and lasted for long. [3]. After 3 hours of kainic acid injection, there was inflammation of dendrites and axons and a reduction of neuronal perikarya and these followed with inflammation signs of the entire brain. [3]. Chemically, there was a diminish level of noradrenaline levels and increased in levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid. [3]. At times there were later reactions (after 24h) following kainic acid injection and in such case, there would be partial death of tissues with loss of nerve cells.[3]. And chemically, there was a reduce level of choline acetyltransferase. [3].

In a mice study, it has been demonstrated that interleukin-18 deficiency eases the activation of microglial in kainic acid-induced toxicity in the brain.[4]. It also showed that interleukin-18 is involved in kainic acid induced hippocampal degeneration. [4]. When there is over activation of glutamate receptors, there is an excess of calcium coming in and thus this leads to damage of neurons. [5]. Activated glial cells and inflammatory molecules can change the result of the disease. [5]. From an endocrinology perspective, kainic acid prevents prolactin production in male rats.[6]. This inhibition is caused by an increase in dopamine production and by a direct effect at the pituitary. [6].Kainic acid’s effect on prolactin production is to some extent reliant on endogenous nitric oxide.[6].

1) https://www.ncbi.nlm.nih.gov/pubmed/10223631
“The activation of glutamate receptors by kainic acid and domoic acid.” Hampson DR1, Manalo JL.

The neurotoxins kainic acid and domoic acid are potent agonists at the kainate and alphaamino-5-methyl-3-hydroxyisoxazolone-4-propionate (AMPA) subclasses of ionotropic glutamate receptors. Although it is well established that AMPA receptors mediate fast excitatory synaptic transmission at most excitatory synapses in the central nervous system, the role of the high affinity kainate receptors in synaptic transmission and neurotoxicity is not entirely clear. Kainate and domoate differ from the natural transmitter, L-glutamate, in their mode of activation of glutamate receptors; glutamate elicits rapidly desensitizing responses while the two neurotoxins elicit non-desensitizing or slowly desensitizing responses at AMPA receptors and some kainate receptors. The inability to produce desensitizing currents and the high affinity for AMPA and kainate receptors are undoubtedly important factors in kainate and domoate-mediated neurotoxicity. Mutagenesis studies on cloned glutamate receptors have provided insight into the molecular mechanisms responsible for these unique properties of kainate and domoate.

2) https://www.hindawi.com/journals/bmri/2011/457079/
“Kainic Acid-Induced Neurodegenerative Model: Potentials and Limitations.” Xiang-Yu Zheng,1,2 Hong-Liang Zhang,2,3 Qi Luo,1 and Jie Zhu2,3

Excitotoxicity is considered to be an important mechanism involved in various neurodegenerative diseases in the central nervous system (CNS) such as Alzheimer's disease (AD). However, the mechanism by which excitotoxicity is implicated in neurodegenerative disorders remains unclear. Kainic acid (KA) is an epileptogenic and neuroexcitotoxic agent by acting on specific kainate receptors (KARs) in the CNS. KA has been extensively used as a specific agonist for ionotrophic glutamate receptors (iGluRs), for example, KARs, to mimic glutamate excitotoxicity in neurodegenerative models as well as to distinguish other iGluRs such as α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and N-methyl-D-aspartate receptors. Given the current knowledge of excitotoxicity in neurodegeneration, interventions targeted at modulating excitotoxicity are promising in terms of dealing with neurodegenerative disorders. This paper summarizes the up-to-date knowledge of neurodegenerative studies based on KA-induced animal model, with emphasis on its potentials and limitations.

3) https://www.ncbi.nlm.nih.gov/pubmed/6141539
“Kainic acid induced seizures: neurochemical and histopathological changes.” Sperk G, Lassmann H, Baran H, Kish SJ, Seitelberger F, Hornykiewicz O. Abstract
Behavioural, histopathological and neurochemical changes induced by systemic injection of kainic acid (10 mg/kg, s.c.) were investigated in rats. The most pronounced behavioural changes were strong immobility ("catatonia"), increased incidence of "wet dog shakes", and long-lasting generalized tonic-clonic convulsions. The behavioural symptoms were fast in their onset and lasted for several hours. Two distinct phases of histopathological and neurochemical changes were observed. (1) Early partially reversible changes were seen up to 3 h after kainic acid injection. They consisted of shrinkage and pyknosis of neuronal perikarya together with swelling of dendrites and axon terminals. These changes were accompanied by generalized signs of edema throughout the whole brain. Neurochemically, there was a marked decrease in noradrenaline levels (up to 70%) and an increase in levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid (up to 200%) in all analysed brain regions, suggesting a strongly increased firing rate of aminergic neurones during the period of generalized seizures. These histological and neurochemical changes were found in all the brain regions examined; they were greatly reduced or only sporadically seen after 1-3 days, when the animals had recovered from the seizures. (2) Late irreversible changes developed 24 h and later following kainic acid injection. They consisted of incomplete tissue necrosis with loss of nerve cells and oligodendrocytes, demyelination, astroglial scar formation, small perivenous hemorrhages and extensive vascular sprouting. The changes were restricted to the pyriform cortex, amygdala, hippocampus (most pronounced in the CA1 sector), gyrus olfactorius lateralis, bulbus olfactorius and tuberculum olfactorium. Neurochemically, a selective decrease was seen in choline acetyltransferase activity (40%) of the amygdala/pyriform cortex area, and of glutamate decarboxylase activity in the dorsal hippocampus (45%) and amygdala/pyriform cortex (55%). No such changes were found in the frontal cortex and the striatum/pallidum. Since at these later time periods the widespread early changes in monoamine metabolism were mostly normalized, loss of acetylcholine and gamma-aminobutyric acid neurons in the affected brain regions represented a selective neurochemical change typical for this stage of kainic acid action. The observed neurochemical and histopathological changes may be directly related to the excitotoxic and convulsive properties of kainic acid. However, brain edema resulting in herniation damage of the basal portions of the brain in addition to disturbances of microcirculation and +

“Kainic acid-induced microglial activation is attenuated in aged interleukin-18 deficient mice” Xing-Mei Zhang, Tao Jin, Hernan Concha Quezada, Eilhard Mix, Bengt Winblad and Jie Zhu.

Previously, we found that interleukin (IL)-18 deficiency aggravates kainic acid (KA)-induced hippocampal neurodegeneration in young C57BL/6 mice due to an over-compensation by IL-12. Additionally, IL-18 participates in fundamental inflammatory processes that increase during aging. In the present study, we were interested in the role of IL-18 in KA-induced neurodegeneration in aged female C57BL/6 mice.
Fifteen aged female IL-18 knockout (KO) and 15 age-matched wild-type (WT) mice (18 to 19 months old) were treated with KA at a dose of 25 mg/kg body weight intranasally. Seizure activities and behavioral changes were rated using a 6-point scoring system and open-field test, respectively. Seven days after KA treatment, degenerating neurons were detected by Nissl's method and Fluoro-Jade B staining; and microglial activation was analyzed by immunohistochemistry and flow cytometry.
Aged female IL-18 KO and WT mice showed similar responses to treatment with KA as demonstrated by comparable seizure activities, behavioral changes and neuronal cell death. However, aged female IL-18 KO mice failed to exhibit the strong microglial activation shown in WT mice. Interestingly, even though the number of activated microglia was less in KA-treated IL-18 KO mice than in KA-treated WT mice, the proportion of microglia that expressed the cytokines tumor necrosis factor (TNF)-α, IL-6 and IL-10 was higher in KA-treated IL-18 KO mice.
Deficiency of IL-18 attenuates microglial activation after KA-induced excitotoxicity in aged brain, while the net effects of IL-18 deficiency are balanced by the enhancement of other cytokines, such as TNF-α, IL-6 and IL-10.

5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131729/
“Kainic Acid-Induced Neurotoxicity: Targeting Glial Responses and Glia-Derived Cytokines.” Xing-Mei Zhang1 and Jie Zhu

Glutamate excitotoxicity contributes to a variety of disorders in the central nervous system, which is triggered primarily by excessive Ca2+ influx arising from overstimulation of glutamate receptors, followed by disintegration of the endoplasmic reticulum (ER) membrane and ER stress, the generation and detoxification of reactive oxygen species as well as mitochondrial dysfunction, leading to neuronal apoptosis and necrosis. Kainic acid (KA), a potent agonist to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate class of glutamate receptors, is 30-fold more potent in neuro-toxicity than glutamate. In rodents, KA injection resulted in recurrent seizures, behavioral changes and subsequent degeneration of selective populations of neurons in the brain, which has been widely used as a model to study the mechanisms of neurodegenerative pathways induced by excitatory neurotransmitter. Microglial activation and astrocytes proliferation are the other characteristics of KA-induced neurodegeneration. The cytokines and other inflammatory molecules secreted by activated glia cells can modify the outcome of disease progression. Thus, anti-oxidant and anti-inflammatory treatment could attenuate or prevent KA-induced neurodegeneration. In this review, we summarized updated experimental data with regard to the KA-induced neurotoxicity in the brain and emphasized glial responses and glia-oriented cytokines, tumor necrosis factor-α, interleukin (IL)-1, IL-12 and IL-18.

6) http://joe.endocrinology-journals.org/content/151/1/159
“Mechanisms of inhibitory action of kainic acid on prolactin secretion in male rats”. L Pinilla, D Gonzalez, M Tena-Sempere, R Aguilar and E Aguilar

Activation of excitatory N-methyl-D-aspartate and kainate receptors evokes multiple and diverse neuroendocrine changes. We have previously shown that kainic acid (KA), an agonist of kainate receptors, inhibits prolactin (PRL) secretion in male rats when given systemically. In the present studies we have characterized this inhibitory action. KA inhibited in vivo PRL secretion in neonatal, prepubertal and adult male rats. This inhibition was independent of gonadal secretion and was evident in male rats whether intact, orchidectomized, or orchidectomized and treated with testosterone. In addition, KA inhibited PRL secretion in male rats rendered hyperprolactinaemic by neonatal administration of oestradiol benzoate. The decrease in serum PRL levels after KA administration was accompanied by an increase in pituitary concentrations of dopamine, and the KA effect on PRL disappeared in males pretreated with domperidone, an antagonist of dopaminergic receptors. These findings strongly suggest that an increase in dopamine release was involved in the effects of KA. Also, KA inhibited in vitro PRL secretion by adenohypophysial dispersed cells and this effect was blocked by 6,7-dinitroquinoxaline, a kainate receptor antagonist, which indicates that the pituitary is also a possible site of action of KA. Nw-nitro-L-arginine-methyl ester, a blocker of nitric oxide synthase, reduced the effects of KA in vivo and slightly stimulated PRL release in vitro.