Midkine, heparin-binding growth factor, blocks kainic acid-induced seizure and neuronal cell death in mouse hippocampus

Yun B Kim,Dongsun Park,Hong J Lee,Jae K Ryu,Seung U Kim,In J Lim,Min C Lee

doi:10.1186/1471-2202-11-42

Abstract

BackgroundMidkine (MK), a member of the heparin-binding growth factor family, which includes MK and pleiotrophin, is known to possess neurotrophic and neuroprotective properties in the central nervous system. Previous studies have shown that MK is an effective neuroprotective agent in reducing retinal degeneration caused by excessive light and decreasing hippocampal neuronal death in ischemic gerbil brain. The present study was undertaken to investigate whether MK acts as an anticonvulsant in kainic acid (KA)-induced seizure in mouse and blocks KA-mediated neuronal cell death in hippocampus.ResultsIncreased expression of MK was found in hippocampus of mouse following seizures induced by intracerebroventricular injection of KA, and MK expression was found in glial fibrillary acidic protein (GFAP)-positive astrocytes. Concurrent injection of MK and KA attenuated KA-induced seizure activity and cell death of hippocampal neurons including pyramidal cells and glutamic acid decarboxylase 67 (GAD67)-positive GABAergic interneurons in the CA3 and hilar area.ConclusionThe results of the present study indicate that MK functions as an anticonvulsant and neuroprotective agent in hippocampus during KA-induced seizures.

Highlights

Midkine (MK), a member of the heparin-binding growth factor family, which includes MK and pleiotrophin, is known to possess neurotrophic and neuroprotective properties in the central nervous system
Previous studies have demonstrated that the animal models of Temporal lobe epilepsy (TLE) generated by intracerebroventricular injection of kainic acid (KA) faithfully reproduce clinical and pathological features found in human TLE [3,4,5,6,7]
Basal level of MK immunoreactivity was found in hippocampal pyramidal neurons in control mouse brain injected with vehicle [phosphate-buffered saline (PBS)] (Figure 1A, top left panel), while in mouse injected with KA decreased MK expression was detected in pyramidal neurons (Figure 1A, bottom left panel; see arrows); Nissl staining of the adjacent sections confirmed that the cellular area of decreased MK immunoreactivity was associated with damaged pyramidal neurons (Figure 1A, bottom right panel; see arrows)

Summary

Introduction

Midkine (MK), a member of the heparin-binding growth factor family, which includes MK and pleiotrophin, is known to possess neurotrophic and neuroprotective properties in the central nervous system. The present study was undertaken to investigate whether MK acts as an anticonvulsant in kainic acid (KA)-induced seizure in mouse and blocks KA-mediated neuronal cell death in hippocampus. Previous studies have demonstrated that the animal models of TLE generated by intracerebroventricular injection of kainic acid (KA) faithfully reproduce clinical and pathological features found in human TLE [3,4,5,6,7]. The objectives of the present study are to determine whether intracerebroventricularly injected MK acts as an anticonvulsant and blocks KA-mediated neuronal cell death in hippocampus MK, a member of the heparin-binding growth factor family, which includes MK and after the brain injury is a part of an endogenous repair process to prevent further damage in the CNS.

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