Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation

Trends Mol Med. 2015 Apr;21(4):245-55. doi: 10.1016/j.molmed.2015.02.002. Epub 2015 Mar 9.


Neuroinflammation is a pathology common to many neurological diseases, including multiple sclerosis (MS) and stroke. However, therapeutic attempts to modulate neuroinflammation have proved difficult. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation. Furthermore, we discuss the mechanisms underlying the beneficial effects of HCA2 activation in neuroinflammatory diseases and the therapeutic potential of recently developed synthetic ligands of HCA2.

Keywords: G protein-coupled receptor; cerebral ischemia; experimental autoimmune encephalomyelitis; hydroxy carboxylic acid receptor; ketogenic diet; multiple sclerosis.

Publication types

  • Review

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology
  • Adenylyl Cyclases / metabolism*
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain Ischemia / drug therapy
  • Diet, Ketogenic*
  • Dimethyl Fumarate / pharmacology
  • Disease Models, Animal
  • Humans
  • Multiple Sclerosis / diet therapy
  • Multiple Sclerosis / drug therapy*
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Neurogenic Inflammation / diet therapy
  • Neurogenic Inflammation / drug therapy*
  • Neuroprotective Agents / therapeutic use
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Niacin / pharmacology
  • Stroke / diet therapy
  • Stroke / drug therapy


  • Neuroprotective Agents
  • Niacin
  • ADCY10 protein, human
  • Adenylyl Cyclases
  • Dimethyl Fumarate
  • 3-Hydroxybutyric Acid