Abstract
BackgroundIn order to confirm the roles of creatine (Cr) in epilepsy, we investigated the anti-convulsive effects of Cr, creatine transporter (CRT) and creatine kinases (CKs) against chemical-induced acute seizure activity and chronic epileptic seizure activity.ResultsTwo hr after pilocarpine (PILO)-seizure induction, ubiquitous mitochondrial CK (uMtCK) immunoreactivity was unaltered as compared to control level. However, brain-type cytoplasm CK (BCK) immunoreactivity was decreased to 70% of control level. CRT immunoreactivity was decreased to 60% of control level. Following Cr or Tat-CK treatment, uMtCK or CRT immunoreactivity was unaffected, while BCK immunoreactivity in Cr treated group was increased to 3.6-fold of control levels. β-Guanidinopropionic acid (GPA, a competitive CRT inhibitor) reduced BCK and CRT expression. In addition, Cr and tat-BCK treatment delayed the beginning of seizure activity after PILO injection. However, GPA treatment induced spontaneous seizure activity without PILO treatment. In chronic epilepsy rats, both uMtCK and CRT immunoreactivities were reduced in the hippocampus. In contrast, BCK immunoreactivity was similar to that observed in control animals. Cr-, GPA and tat-BCK treatment could not change EEG.ConclusionCr/CK circuit may play an important role in sustaining or exacerbating acute seizure activity, but not chronic epileptic discharge.
Highlights
In order to confirm the roles of creatine (Cr) in epilepsy, we investigated the anti-convulsive effects of Cr, creatine transporter (CRT) and creatine kinases (CKs) against chemical-induced acute seizure activity and chronic epileptic seizure activity
The effects of PILO-induced seizure activity on CK and CRT expressions in the rat hippocampus In saline-treated animals, ubiquitous mitochondrial CK (uMtCK) immunoreactivity was observed in CA1-3 pyramidal cells, dentate granule cells and hilar neurons (Figures 1A)
The properties of reactive astrocyte are different from those of naive astrocyte [34,35,38,50] Taken together with preservation of brain-type cytoplasm CK (BCK) expression in reactive astrocytes, our findings suggest that maintenance of Cr-PCr/CK circuit in reactive astrocytes may be involved in migration, proliferation and differentiation of reactive astrocytes in epileptic hippocampus described in previous studies [34,38,50]
Summary
In order to confirm the roles of creatine (Cr) in epilepsy, we investigated the anti-convulsive effects of Cr, creatine transporter (CRT) and creatine kinases (CKs) against chemical-induced acute seizure activity and chronic epileptic seizure activity. It is generally assumed that most energy required in the nervous system is provided in the form of adenosine triphosphate (ATP) by mitochondria [3]. Astrocytes have been shown to synthesize creatine from glycine added to culture media [17]. Phosphate transfer reaction between Cr and PCr is reversibly catalyzed by creatine kinases (CKs) present in the mitochondria and cytoplasm [18]. CKs have an energy protective role in the brain. PCr/Cr loading has been demonstrated by showing beneficial effects of Cr-feeding in children with inborn errors in Cr transport [22]
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