TY - JOUR

T1 - Neuroprotective Effects of Ceftriaxone Involve the Reduction of Aβ Burden and Neuroinflammatory Response in a Mouse Model of Alzheimer’s Disease

AU - Tikhonova, Maria A.

AU - Amstislavskaya, Tamara G.

AU - Ho, Ying Jui

AU - Akopyan, Anna A.

AU - Tenditnik, Michael V.

AU - Ovsyukova, Marina V.

AU - Bashirzade, Alim A.

AU - Dubrovina, Nina I.

AU - Aftanas, Lyubomir I.

N1 - Publisher Copyright: © Copyright © 2021 Tikhonova, Amstislavskaya, Ho, Akopyan, Tenditnik, Ovsyukova, Bashirzade, Dubrovina and Aftanas.

PY - 2021/9/29

Y1 - 2021/9/29

N2 - Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer’s disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aβ) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aβ deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aβ. Mice were injected bilaterally i.c.v. with Aβ fragment 25–35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aβ neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.

AB - Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer’s disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aβ) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aβ deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aβ. Mice were injected bilaterally i.c.v. with Aβ fragment 25–35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aβ neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.

KW - amyloid

KW - behavior

KW - cognition

KW - drug repurposing

KW - microglia

KW - neurodegeneration

UR - http://www.scopus.com/inward/record.url?scp=85117142489&partnerID=8YFLogxK

U2 - 10.3389/fnins.2021.736786

DO - 10.3389/fnins.2021.736786

M3 - Article

C2 - 34658774

AN - SCOPUS:85117142489

VL - 15

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-4548

M1 - 736786

ER -