Cerebellar and cortical TLR4 activation and behavioral impairments in Wernicke-Korsakoff Syndrome: Pharmacological effects of oleoylethanolamide

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jun 8:108:110190. doi: 10.1016/j.pnpbp.2020.110190. Epub 2020 Dec 1.

Abstract

Wernicke-Korsakoff Syndrome (WKS) is a neuropsychiatric disorder whose etiology is a thiamine deficiency (TD), with alcoholism being the main underlying cause. Previous evidence suggests the presence of initial neuroinflammation and oxidative/nitrosative stress in the physiopathology, although the specific molecular mechanisms underlying TD-induced brain damage and behavioral disabilities are unknown. We explored the specific role of the innate immune receptor TLR4 in three murine models of WKS, based on the combination of a thiamine-deficient diet and pyrithiamine injections (0.25 mg/kg, i.p.) over time. The Symptomatic Model (SM) allowed us to describe the complete neurological/neurobehavioral symptomatology over 16 days of TD. Animals showed an upregulation of the TLR4 signaling pathway both in the frontal cortex (FC) and cerebellum and clear motor impairments related with cerebellar dysfunction. However, in the Pre-Symptomatic Model (PSM), 12 days of TD induced the TLR4 pathway upregulation in the FC, which correlated with disinhibited-like behavior, but not in the cerebellum, and no motor impairments. In addition, we tested the effects of the biolipid oleoylethanolamide (OEA, 10 mg/kg, i.p., once daily, starting before any symptom of the pathology is manifested) through the Glucose-Precipitated Model (GPM), which was generated by glucose loading (5 g/kg, i.v., last day) in thiamine-deficient animals to accelerate damage. Pretreatment with OEA prevented the TLR4-induced signature in the FC, as well as an underlying incipient memory disability and disinhibited-like behavior. This study suggests a key role for TLR4 in TD-induced neuroinflammation in the FC and cerebellum, and it reveals different vulnerability of these brain regions in WKS over time. Pre-treatment with OEA counteracts TD-induced TLR4-associated neuroinflammation and may serve as co-adjuvant therapy to prevent WKS-induced neurobehavioral alterations.

Keywords: Cerebellum; Frontal cortex; Innate immunity; Oleoylethanolamide; Thiamine deficiency; Wernicke-Korsakoff syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / chemistry
  • Cerebellum / metabolism*
  • Cerebral Cortex / chemistry
  • Cerebral Cortex / metabolism*
  • Cytokines / analysis
  • Cytokines / metabolism
  • Disease Models, Animal
  • Elevated Plus Maze Test
  • Endocannabinoids / therapeutic use*
  • Korsakoff Syndrome / drug therapy*
  • Male
  • Neuroinflammatory Diseases / drug therapy
  • Neuroinflammatory Diseases / etiology
  • Oleic Acids / therapeutic use*
  • Open Field Test
  • Rats
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • Rotarod Performance Test
  • Thiamine Deficiency / complications
  • Toll-Like Receptor 4 / analysis
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Cytokines
  • Endocannabinoids
  • Oleic Acids
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • oleoylethanolamide