Inhibition of protease-activated receptor 1 (PAR1) ameliorates cognitive performance and synaptic plasticity impairments in animal model of Alzheimer’s diseases

• Published in: Psychopharmacology 2021-06, Vol.238 (6), p.1645-1656
• Main Authors: Zare, Daruoosh, Rajizadeh, Mohammad Amin, Maneshian, Marzieh, Jonaidi, Hossein, Sheibani, Vahid, Asadi-Shekaari, Majid, Yousefi, Manouchehr, Esmaeilpour, Khadijeh
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animal models; Biomedical and Life Sciences; Biomedicine; Cognitive ability; Drug therapy; Excitatory postsynaptic potentials; Genetic aspects; Hippocampus; Injection; Long-term potentiation; Memory; Neurodegenerative diseases; Neurosciences; Original Investigation; Pattern recognition; Pharmacology/Toxicology; Protease inhibitors; Proteinase-activated receptor 1; Psychiatry; Spatial discrimination learning; Spatial memory; Stratum radiatum; Synaptic plasticity; Testing; Thrombin
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-05798-8

Introduction Alzheimer’s disease (AD) is a progressive brain disorder accompanied with synaptic failures and decline in cognitive and learning processes. Protease-activated receptor 1 (PAR1) is the major thrombin receptor in the brain that is implicated in synaptic plasticity and memory formation. In the current study, we hypothesized that inhibition of PAR1 would theoretically prevent amyloid beta (Aβ) accumulation in the brain and then contribute to reduce risk of AD. The aim of the present study was to evaluate the effect of PAR1 inhibition by using SCH (as an inhibitor of PAR1) on spatial learning, memory, and synaptic plasticity in the CA1 region of the hippocampus in rat model of Alzheimer’s disease. Methods For the induction of Alzheimer’s disease, amyloid beta (Aβ) 1–42 was injected in the CA1 region of the hippocampus. The rats were divided into four groups: group I (surgical sham); group II rat mode of Alzheimer’s disease (AD); group III (SCH) (25 μg/kg) intraperitoneally (i.p.), and group IV (AD + SCH). After 14 days of protocol, the rats in group III received SCH and 30 min after injection behavioral and electrophysiological tests were performed. Learning and memory ability was assessed by Morris water maze and novel object recognition tests. Extracellular evoked field excitatory postsynaptic potentials (fEPSP) were recorded in the stratum radiatum of the CA1 area. Results Our results showed that AD rats showed impairments in learning and memory, and long-term potentiation (LTP) was not induced in these rats. However, injection of SCH overcame the AD-induced impairment in LTP generation in the CA1 area of the hippocampus and improved learning and memory impairment.