RT Journal Article
T1 Cerebellar and cortical TLR4 activation and behavioral impairments in Wernicke-Korsakoff Syndrome: Pharmacological effects of oleoylethanolamide
A1 Moya Montes, Marta
A1 San Felipe Riba, Diego
A1 Ballesta, Javier Antonio
A1 Alén Fariñas, Francisco
A1 Rodríguez De Fonseca, Fernando Antonio
A1 García Bueno, Borja
A1 Marco López, Eva María
A1 Orio Ortiz, Laura
AB 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.
PB Elsevier
SN 0278-5846
YR 2020
FD 2020-12-01
LK https://hdl.handle.net/20.500.14352/8012
UL https://hdl.handle.net/20.500.14352/8012
LA eng
NO Ministerio de Ciencia e Innovación (MICINN)/Fondo Europeo de Desarrollo Regional (FEDER)
NO Instituto de Salud Carlos III (ISCIII). Programa RETICS: Red de Trastornos Adictivos
NO Universidad Complutense de Madrid (UCM)
DS Docta Complutense
RD 6 abr 2025