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. 2011 Jun;9(2):388-98.
doi: 10.2174/157015911795596540.

Kainic Acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines

Xing-Mei Zhang  1 , Jie Zhu
Affiliations

Kainic Acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines

Xing-Mei Zhang et al. Curr Neuropharmacol. 2011 Jun.

Abstract

Glutamate excitotoxicity contributes to a variety of disorders in the central nervous system, which is triggered primarily by excessive Ca(2+) 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.

Keywords: Kainic acid; astrocytes; cytokines.; excitotoxicity; microglia.

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Figures

Fig. (1)
Fig. (1)
The Input and Output Pathways of Hippocampal Formation. Entorhinal cortex (EC) is the main input to the hippocampus. EC projects to the dentate gyrus (DG) via perforant fiber pathway and provides the critical input to CA3 via mossy fiber pathway, then to CA1 by means of the Schaffer collateral pathway. Additionally, EC can also project directly to CA3, CA1 and subiculum (Sub). Meantime, EC is the major output of the hippocampus. Arrows denote the direction of impulse flow.
Fig. (2)
Fig. (2)
Schematic Overview of KA-Mediated Neuronal Death. (1) By stimulating glutamate receptors (GluR), kainic acid (KA) elicits the increase of intracellular Ca2+, activation of Ca2+-dependent enzyme and production of free radicals; (2) Excessive Ca2+ and free radicals cause mitochondrial dysfunction, release of mitochondrial factors, activation of caspase-3, leading to neuronal apoptosis; (3) KA causes the disintegration of the endoplasmic reticulum (ER) and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12, involved in neuronal apoptosis; (4) Ca2+ overload and excessive free radicals cause directly mitochondrial swelling, leading to neuronal necrosis. COX: cyclooxygenase; ROS: reactive oxygen species; RNS: reactive nitrogen species.
Fig. (3)
Fig. (3)
Glial cells activation accompanied the neuronal death 7 days after KA (45 mg/kg body weight) treatment to C57BL/6 mice. (A) Obvious neuronal loss was showed in CA3 area of hippocampus by Nissl’s staining. (B) CD11b positive cells (microglia) accumulated in the lesioned CA3 area. (C) GFAP positive cells (astrocytes) spread the whole hippocampus, especially in CA3 area. Arrows in A indicate the areas of neuronal loss.
Fig. (4)
Fig. (4)
The Categories of Molecules Produced by Activated Microglia. IL: interleukin; TNF: tumor necrosis factor; TGF: transforming growth factor; IL-1ra: IL-1 receptor antagonist; MIP: macrophage inflammatory protein; MDC: macrophage-derived chemokine; MCP: monocyte-chemoattractant protein; RANTES: regulated on activation normal T cell expressed and secreted; IFN: interferon; IP: IFN-inducible protein; R: receptor; NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; NT: neurotrophin; MHC: major histocompatibility complex; CR: complement receptor; C1qRp: C1q receptor for phagocytosis enhancement; FasL: Fas ligand; PG: prostaglandin; COX: cyclooxygenase; NO: nitric oxide; ROS: reactive oxygen species; RNS: reactive nitrogen species; MMP: matrix metalloproteinase; NSAIDs: nonsteroidal antiinflammatory drugs.
Fig. (5)
Fig. (5)
The Categories of Molecules Produced by Activated Astrocytes. ROS: reactive oxygen species; IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; CSF: colony-stimulating factor; GM-CSF: granulocyte-macrophage CSF; TGF: transforming growth factor; MCP: monocyte-chemoattractant protein; RANTES: regulated on activation normal T cell expressed and secreted; IP: IFN-inducible protein; NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; bFGF: basic fibroblast growth factor; MMP: matrix metalloproteinase.
Fig. (6)
Fig. (6)
Cytokines Involved in Neuron-glia Intercommunication. KA administration enhances further release of endogenous excitatory amino acids, activates microglia and astrocytes. Activated glial cells secrete inflammatory molecules, e.g. cytokines, chemokines, and neurotrophins to influence the outcome of neuronal damage. Glu/KA: glutamate/kainic acid; GluR: glutamate receptors; TGF: transforming growth factor; IL: interleukin; TNF: tumor necrosis factor.
Fig. (7)
Fig. (7)
Schematic Illustration of Anti-Oxidant and Anti-inflammatory Treatments. By inhibiting one of the major components of the neuroinflammatory response after KA treatment, there could be less inflammation and neuronal loss. The potential treatments include (1) cyclooxygenase (COX)-2 inhibitors and other antioxidants; (2) Phospholipase A2 inhibitors; (3) Free radical scavengers; (4) endoplasmic reticulum (ER) stress inhibitors; and (5) Glia-derived cytokines. Glu/KA: glutamate/kainic acid; GluR: glutamate receptors; ROS: reactive oxygen species; RNS: reactive nitrogen species.
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