Cannabidiol attenuates cognitive deficits and neuroinflammation induced by early alcohol exposure in a mice model

Abstract

Foetal alcohol spectrum disorder (FASD) is the umbrella term used to describe the physical and mental disabilities induced by alcohol exposure during development. Early alcohol exposure induces cognitive impairments resulting from damage to the central nervous system (CNS). The neuroinflammatory response accompanied by neurodegenerative mechanisms contribute to those detrimental alterations. Cannabidiol (CBD) has recently emerged as an anti-inflammatory drug that might be useful to treat several neuropsychiatric disorders. In our study, we assessed the effects of CBD on long-lasting cognitive deficits induced by early alcohol exposure. Furthermore, we analysed long-term pro-inflammatory and apoptotic markers within the prefrontal cortex and hippocampus. To model alcohol binge drinking during gestational and lactation periods, we used pregnant C57BL/6 female mice with time-limited access to 20% v/v alcohol solution. Following the prenatal and lactation alcohol exposure (PLAE), we treated the male and female offspring with CBD from post-natal day (PD) 25 until PD34, and we evaluated their cognitive performance at PD60. Our results showed that CBD treatment during peri-adolescence period ameliorates cognitive deficits observed in our FASD-like mouse model, without sex differences. Moreover, CBD restores the PLAE-induced increased levels of TNFα and IL-6 in the hippocampus. Thus, our study provides new insights for CBD as a therapeutic agent to counteract cognitive impairments and neuroinflammation caused by early alcohol exposure.

PPAR-γ is a promising therapeutic target for memory deficits induced by early alcohol exposure

“…First, using a validated PLAE mouse model (3,9), we report that persistent memory impairments are accompanied by alterations in the expanded ECS. At an early life stage (PD25), we observed a reduction of CB1 and PPAR-γ expression, as well as reduced levels of OEA, PEA, DEA and DHEA in the HPC of PLAE mice.…”

“…The Drinking in the Dark (DID) procedure was conducted as previously reported (3,9) to model a prenatal and lactation alcohol exposure under a binge-like drinking pattern. After the weaning, we performed four different experiments in PLAE and control (water-exposed) offspring: i) analyses of molecules of the expanded ECS in the HPC and PFC at PD25 and PD70.…”

“…Even though studies of perinatal alcohol exposure on non-canonical molecules of the expanded ECS are limited, some evidence does suggest that this complex system might provide new therapeutic opportunities for FASD. On the one hand, the administration of cannabidiol, which acts on multiple targets of the expanded ECS including NAEs and PPAR-γ, ameliorates cognitive deficits in a FASD-like mouse model (9,26) and in FASD patients (27,28). On the other hand, resveratrol, a natural PPAR-γ agonist, attenuated cognitive impairments in a preclinical model of FASD (29).…”

“…Perinatal alcohol exposure disrupts major developmental processes, like neuro-and gliogenesis, migration, proliferation, synaptogenesis and myelination (3)(4)(5)(6), consequently impairing synaptic plasticity, circuit formation, learning and memory (7). These molecular and behavioral alterations are physiologically irreversible and persistent (8)(9)(10)(11). Therefore, an early intervention during critical periods of high brain plasticity could facilitate the resolution of the disrupted processes on time and ameliorate the prognosis.…”

Effect of long-term cannabidiol on learning and anxiety in a female Alzheimer’s disease mouse model

“…Furthermore, remedial CBD treatment (i.e., after the development of cognitive deficits) affects different domains in male and female APPxPS1 mice: CBD improves social recognition, object recognition, and spatial reversal learning in male APPxPS1 mice (Cheng et al, 2014a;Watt et al, 2020a) but only object recognition deficits in female APPxPS1 mice (Coles et al, 2020). Indeed, there has been limited investigation of sex differences in CBD's effects on anxiety-like behaviour and cognition, e.g., (Osborne et al, 2017;Osborne et al, 2019;Garcia-Baos et al, 2021), highlighting the importance of examining female and male animals. Thus, we sought to determine if preventive CBD affects different behavioural domains in male and female APPxPS1 mice.…”