Naringenin ameliorates kainic acid-induced morphological alterations in the dentate gyrus in a mouse model of temporal lobe epilepsy

Neuroreport. 2016 Oct 19;27(15):1182-9. doi: 10.1097/WNR.0000000000000678.

Abstract

Granule cell dispersion (GCD) in the dentate gyrus (DG) of the hippocampus is a morphological alteration characteristic of temporal lobe epilepsy. Recently, we reported that treatment with naringin, a flavonoid found in grapefruit and citrus fruits, reduced spontaneous recurrent seizures by inhibiting kainic acid (KA)-induced GCD and neuronal cell death in mouse hippocampus, suggesting that naringin might have beneficial effects for preventing epileptic events in the adult brain. However, it is still unclear whether the beneficial effects of naringin treatment are mediated by the metabolism of naringin into naringenin in the KA-treated hippocampus. To investigate this possibility, we evaluated whether intraperitoneal injections of naringenin could mimic naringin-induced effects against GCD caused by intrahippocampal KA injections in mice. Our results showed that treatment with naringenin delayed the onset of KA-induced seizures and attenuated KA-induced GCD by inhibiting activation of the mammalian target of rapamycin complex 1 in both neurons and reactive astrocytes in the DG. In addition, its administration attenuated the production of proinflammatory cytokines such as tumor necrosis tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) from microglial activation in the DG following KA treatment. These results suggest that naringenin may be an active metabolite of naringin and help prevent the progression of epileptic insults in the hippocampus in vivo; therefore, naringenin may be a beneficial metabolite of naringin for the treatment of epilepsy.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Anticonvulsants / therapeutic use*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cytokines
  • Dentate Gyrus / drug effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epilepsy, Temporal Lobe / chemically induced
  • Epilepsy, Temporal Lobe / drug therapy*
  • Epilepsy, Temporal Lobe / pathology*
  • Eukaryotic Initiation Factors
  • Excitatory Amino Acid Agonists / toxicity
  • Flavanones / therapeutic use*
  • Kainic Acid / toxicity
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Nerve Tissue Proteins / metabolism
  • Phosphoproteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Anticonvulsants
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cytokines
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Excitatory Amino Acid Agonists
  • Flavanones
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Mechanistic Target of Rapamycin Complex 1
  • naringenin
  • Kainic Acid