Tohoku J. Exp. Med., 2014 April, 232(4)

Reduction in Glutamine/Glutamate Levels in the Cerebral Cortex after Adrenocorticotropic Hormone Therapy in Patients with West Syndrome

MITSUTOSHI MUNAKATA,¹ NORIKO TOGASHI,² OSAMU SAKAMOTO,¹ KAZUHIRO HAGINOYA,³ YASUKO KOBAYASHI,⁴ AKIRA ONUMA,³ KAZUIE IINUMA¹ and SHIGEO KURE¹

¹Department of Pediatrics, Tohoku University School of Medicine, Sendai, Miyagi, Japan
²Department of Neurology, Miyagi Children's Hospital, Sendai, Miyagi, Japan
³Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Miyagi, Japan
⁴Department of Pediatrics, Sendai Nishitaga National Hospital, Sendai, Miyagi, Japan

West syndrome (WS), an intractable epileptic encephalopathy of infancy, is refractory to many antiepileptic drugs; however, adrenocorticotropic hormone (ACTH) is an effective treatment for WS. The mechanism behind the efficacy of ACTH is mediated by biochemical processes that remain unknown. We examined the effects of ACTH therapy with tetracosactide (TCS), a synthetic ACTH analogue, on brain metabolism in patients with WS, using ¹H magnetic resonance spectroscopy (¹H-MRS). In six patients with cryptogenic WS, we performed single-voxel ¹H-MRS at the occipital lobe cortex. Measurements were taken prior to TCS treatment, a few days after therapy, and several months after therapy. Data were also compared with subjects having only mild psychomotor delays. The metabolites measured were glutamine plus glutamate (Glx), N-acetylaspartate (NAA), choline (Cho), and myoinositol (mI); each was expressed as a ratio with creatine plus phosphocreatine (total creatine: tCr). The Glx/tCr ratio was significantly reduced after the TCS treatment. The NAA/tCr ratio was also significantly reduced after the treatment compared with the control group, although the change in NAA signal was heterogeneous among patients, correlating with respective outcomes. The Cho/tCr and mI/tCr ratios were not affected by TCS treatment. The reduction in Glx suggests a decrease in the glutamate-glutamine cycle, which plays a pivotal role in synthesizing neurotransmitters such as glutamate and GABA. TCS-induced Glx reduction may induce changes in synaptic signal transduction, thereby accounting for the effect of TCS on WS. The change in NAA indicates altered neuronal activity, which may be correlated with outcome in WS patients.

keywords —— adrenocorticotropic hormone; glutamine-glutamate cycle; ¹H magnetic resonance spectroscopy; tetracosactide; West syndrome

© 2014 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2014, 232, 277-283

Correspondence: Mitsutoshi Munakata, M.D., Ph.D., Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: m-munakata@umin.ac.jp