Naringin Attenuates Autophagic Stress and Neuroinflammation in Kainic Acid-Treated Hippocampus In Vivo

Kainic acid (KA) is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS) in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3), and attenuated an increase in tumor necrosis factor-α (TNFα) in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo.

[1]  K. Vafeiadou,et al.  The neuroprotective potential of flavonoids: a multiplicity of effects , 2008, Genes & Nutrition.

[2]  D. Saluja,et al.  Naringin protects against kainic acid-induced status epilepticus in rats: evidence for an antioxidant, anti-inflammatory and neuroprotective intervention. , 2011, Biological & pharmaceutical bulletin.

[3]  Á. Simonyi,et al.  Kainic acid-mediated excitotoxicity as a model for neurodegeneration , 2007, Molecular Neurobiology.

[4]  R. Sankar,et al.  Inflammation enhances epileptogenesis in the developing rat brain , 2010, Neurobiology of Disease.

[5]  C. Hamani,et al.  Changes in Hippocampal Volume are Correlated with Cell Loss but Not with Seizure Frequency in Two Chronic Models of Temporal Lobe Epilepsy , 2014, Front. Neurol..

[6]  Philippe Dessen,et al.  Inhibition of Macroautophagy Triggers Apoptosis , 2005, Molecular and Cellular Biology.

[7]  Wei Wang,et al.  Excitotoxicity of TNFα derived from KA activated microglia on hippocampal neurons in vitro and in vivo , 2010, Journal of neurochemistry.

[8]  N Guthrie,et al.  Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. , 1996, Nutrition and cancer.

[9]  Tallie Z. Baram,et al.  The role of inflammation in epilepsy , 2011, Nature Reviews Neurology.

[10]  R. Burke,et al.  In vivo AAV1 transduction with hRheb(S16H) protects hippocampal neurons by BDNF production. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[11]  Chi Li,et al.  Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis , 2005, Cell.

[12]  G. Yen,et al.  Neuroprotective effects of citrus flavonoids. , 2012, Journal of agricultural and food chemistry.

[13]  A. Vezzani,et al.  Functional Role of Inflammatory Cytokines and Antiinflammatory Molecules in Seizures and Epileptogenesis , 2002, Epilepsia.

[14]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[15]  I. Módy,et al.  The process of epileptogenesis: a pathophysiological approach , 2001, Current opinion in neurology.

[16]  Z. Qin,et al.  An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid , 2008, Autophagy.

[17]  Anil Kumar,et al.  Protective effect of naringin against ischemic reperfusion cerebral injury: possible neurobehavioral, biochemical and cellular alterations in rat brain. , 2009, European journal of pharmacology.

[18]  Jie Zhu,et al.  Kainic Acid-Induced Neurodegenerative Model: Potentials and Limitations , 2010, Journal of biomedicine & biotechnology.

[19]  G. Sudhandiran,et al.  Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway , 2012, Neuroscience.

[20]  K. Roth,et al.  Kainic acid induces early and transient autophagic stress in mouse hippocampus , 2007, Neuroscience Letters.

[21]  Sang-Joon Park,et al.  Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease. , 2014, The Journal of nutritional biochemistry.

[22]  A. Cuervo,et al.  Autophagy gone awry in neurodegenerative diseases , 2010, Nature Neuroscience.

[23]  A. Vezzani,et al.  Brain Inflammation in Epilepsy: Experimental and Clinical Evidence , 2005, Epilepsia.

[24]  Ji-Seon Seo,et al.  Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus , 2009, Brain Research.

[25]  V. Perry,et al.  The kinetics and morphological characteristics of the macrophage-microglial response to kainic acid-induced neuronal degeneration , 1991, Neuroscience.

[26]  Lianfeng Zhang,et al.  Long-term naringin consumption reverses a glucose uptake defect and improves cognitive deficits in a mouse model of Alzheimer's disease , 2012, Pharmacology Biochemistry and Behavior.