4月22日担当の薬理学講座の川村です。
以下の論文を紹介いたします。
Hydroxycarboxylic Acid Receptor 2 Mediates β-hydroxybutyrate’s
Antiseizure Effect in Mice
Soudabeh Naderi, John Williamson, Huayu Sun, Suchitra Joshi, Rachel Jane
Spera, Savaira Zaib, Supriya Sharma, Chengsan Sun, Andrey Brodovskiy,
Ifrah Zawar, Jaideep Kapur
Ann Neurol, 99: 809-824. doi.org/10.1002/ana.78098
Abstract
Objective: The ketogenic diet, a high-fat, low-carbohydrate regimen, is
often used to treat drug-resistant seizures and is being studied for
Alzheimer’s disease and other neuropsychiatric disorders. However, its
mechanism of action remains unclear. β-hydroxybutyrate, a primary
circulating ketone body produced by the ketogenic diet, may mediate its
effects on seizures by binding to a recently identified Gi-coupled
receptor: hydrocarboxylic acid receptor 2 (HCAR2).
Methods: RNAscope in situ hybridization assay and real-time quantitative
polymerase chain reaction were used to assess HCAR2 expression in the
mouse brain. We generated HCAR2-/- using the CRISPR-Cas technique on an
S129 mouse background. Whole-cell current-clamp was performed to measure
the passive and active membrane properties of hippocampal dentate
granule cells. The voltage-clamp was performed to record synaptic
currents. Two complementary in vivo mouse models-continuous hippocampal
stimulation to induce status epilepticus (SE) and kindling-were used to
induce seizures.
Results: HCAR2 was localized in dentate granule cells and microglia. In
mice with HCAR2, β-hydroxybutyrate reduced neuronal excitability by
hyperpolarizing the resting membrane potential, raising the action
potential threshold, and reducing the firing frequency of dentate
granule cells. β-hydroxybutyrate suppressed excitatory synaptic
transmission. These effects were nullified in HCAR2-/- mice. HCAR2-/-
mice showed no cognitive impairment. Moreover, β-hydroxybutyrate did not
affect seizures in HCAR2-/- mice. However, it diminished both the
duration and severity of seizures in HCAR2+/+ mice.
Interpretation: These findings demonstrate that HCAR2 mediates
β-hydroxybutyrate’s antiseizure effects by regulating neuronal
excitability and synaptic transmission. These studies propose a new
mechanism for the antiseizure action of the ketogenic diet.
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薬理学講座 川村将仁