Neuroprotective effect of low-dose paracetamol treatment against cognitive dysfunction in d-galactose-induced aging mice

Laddawan Lalert; Supang Maneesri le-Grand; Tachpon Techarang; Soontaraporn Huntula; Chuchard Punsawad

doi:10.1016/j.heliyon.2022.e11108

Neuroprotective effect of low-dose paracetamol treatment against cognitive dysfunction in d-galactose-induced aging mice

Heliyon. 2022 Oct 15;8(10):e11108. doi: 10.1016/j.heliyon.2022.e11108. eCollection 2022 Oct.

Authors

Laddawan Lalert^{1

2}, Supang Maneesri le-Grand³, Tachpon Techarang^{1

2}, Soontaraporn Huntula^{4

2}, Chuchard Punsawad^{1

2}

Affiliations

¹ Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand.
² Research Center in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat 80160, Thailand.
³ Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
⁴ Department of Sport and Exercise Science, School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand.

Abstract

Background: Aging is closely associated to several deleterious conditions and cognitive impairment. Administration of low-dose paracetamol (APAP) has previously been reported to improve cognitive performance in both human and animal studies. However, the altered cognitive effects of low-dose APAP treatment in the aging brain have not been elucidated.

Objectives: The purpose of this study was to determine whether low-dose APAP treatment improves cognitive dysfunction in a d-galactose (d-gal)-induced aging model.

Materials and methods: APAP (15 and 50 mg/kg p.o.) and vitamin E (Vit E 100 mg/kg p.o.) were administered once daily to d-gal-injected mice (200 mg/kg s.c.) for 6 weeks. The elevated plus maze (EPM), open field, novel object recognition (NOR), and Morris water maze (MWM) tests, respectively, were used to measure altered neurobehavioral functions, including anxiety-like behavior and exploratory locomotor activity, as well as learning and memory performance. The gene transcription of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in brain tissues was evaluated by real-time polymerase chain reaction.

Results: Compared to the control, d-gal significantly decreased exploratory locomotor activity and NOR and MWM performance but did not significantly change the activity in the EPM test. However, APAP50 and Vit E significantly reversed the effects of d-gal injection on exploratory locomotor activity. In addition, low-dose APAP (15 and 50 mg/kg) and Vit E significantly improved the reduction in NOR and MWM performance induced by d-gal. Real-time polymerase chain reaction analysis revealed that the mRNA expression of BDNF, neurotrophic tyrosine receptor kinase (NTRK), which is the gene coding TrkB receptor, and cAMP response element-binding protein (CREB) was significantly decreased in the frontal cortex and hippocampus of the d-gal mice. However, APAP50 and Vit E significantly increased BDNF and NTRK mRNA expression in both the frontal cortex and the hippocampus. A lower dose of APAP (15 mg/kg) significantly elevated the mRNA expression of NTRK, but only in the hippocampus. Moreover, APAP50 significantly increased CREB mRNA expression in the frontal cortex and hippocampus.

Conclusion: Low-dose APAP treatment has a neuroprotective effect on cognitive dysfunction in the d-gal aging model, and the underlying molecular mechanisms depend on the activation of BDNF/TrkB signaling.

Keywords: Aging; BDNF/TrkB signaling; Cognitive dysfunction; Paracetamol; d-galactose.