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The hydroxycarboxylic acid receptor HCA2 is required for the protective effect of ketogenic diet in epilepsy

Jill C Richardson1, Guy A Higgins2, Neil Upton3

  • 1Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D Ltd, Stevenage, UK.

Pharmacology Research & Perspectives
|October 23, 2024
PubMed

Insights

The hydroxycarboxylic acid receptor 2 (HCA2) may mediate the anti-seizure effects of the ketogenic diet. Targeting HCA2 with agonists shows promise for treating refractory epilepsy and neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Metabolic Disorders

Background:

  • Epilepsy affects millions, with one-third of patients exhibiting resistance to anti-seizure medications.
  • The ketogenic diet is an established therapy for refractory epilepsy, yet its underlying mechanisms remain unclear.
  • Hydroxycarboxylic acid receptor 2 (HCA2) is an immunomodulatory receptor implicated in various physiological processes.

Purpose of the Study:

  • To investigate the role of HCA2 in mediating the anticonvulsant effects of the ketogenic diet.
  • To explore HCA2 agonists as a potential therapeutic strategy for epilepsy.

Main Methods:

  • Utilized animal models (6Hz seizure model) and ex vivo rodent and human brain slices.
  • Administered selective HCA2 agonists and studied ketogenic diet effects in HCA2-deficient mice.
  • Measured seizure frequency and network activity.

Main Results:

  • Selective HCA2 agonists demonstrated direct seizure reduction in animal models.
  • HCA2 agonists decreased aberrant network activity in rodent and human brain slices.
  • The anticonvulsant effect of the ketogenic diet was abolished in HCA2-deficient mice, indicating HCA2's crucial role.

Conclusions:

  • HCA2 is a key mediator of the ketogenic diet's protective effects against seizures.
  • Targeting HCA2 represents a promising therapeutic avenue for drug-resistant epilepsy.
  • HCA2 modulation may also hold potential for treating neurodegenerative diseases.
Keywords:
EpilepsyGSK256073HCA2Hydroxycarboxylic acid receptorKetogenic Diet

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