Cannabidivarin Treatment Ameliorates Autism-Like Behaviors and Restores Hippocampal Endocannabinoid System and Glia Alterations Induced by Prenatal Valproic Acid Exposure in Rats

Abstract

Autism spectrum disorder (ASD) is a developmental condition whose primary features include social communication and interaction impairments with restricted or repetitive motor movements. No approved treatment for the core symptoms is available and considerable research efforts aim at identifying effective therapeutic strategies. Emerging evidence suggests that altered endocannabinoid signaling and immune dysfunction might contribute to ASD pathogenesis. In this scenario, phytocannabinoids could hold great pharmacological potential due to their combined capacities to act either directly or indirectly on components of the endocannabinoid system and to modulate immune functions. Among all plant-cannabinoids, the phytocannabinoid cannabidivarin (CBDV) was recently shown to reduce motor impairments and cognitive deficits in animal models of Rett syndrome, a condition showing some degree of overlap with autism, raising the possibility that CBDV might have therapeutic potential in ASD. Here, we investigated the ability of CBDV treatment to reverse or prevent ASD-like behaviors in male rats prenatally exposed to valproic acid (VPA; 500 mg/kg i.p.; gestation day 12.5). The offspring received CBDV according to two different protocols: symptomatic (0.2/2/20/100 mg/kg i.p.; postnatal days 34–58) and preventative (2/20 mg/kg i.p.; postnatal days 19–32). The major efficacy of CBDV was observed at the dose of 20 mg/kg for both treatment schedules. CBDV in symptomatic rats recovered social impairments, social novelty preference, short-term memory deficits, repetitive behaviors and hyperlocomotion whereas preventative treatment reduced sociability and social novelty deficits, short-term memory impairments and hyperlocomotion, without affecting stereotypies. As dysregulations in the endocannabinoid system and neuroinflammatory markers contribute to the development of some ASD phenotypes in the VPA model, neurochemical studies were performed after symptomatic treatment to investigate possible CBDV’s effects on the endocannabinoid system, inflammatory markers and microglia activation in the hippocampus and prefrontal cortex. Prenatal VPA exposure increased CB1 receptor, FAAH and MAGL levels, enhanced GFAP, CD11b, and TNFα levels and triggered microglia activation restricted to the hippocampus. All these alterations were restored after CBDV treatment. These data provide preclinical evidence in support of the ability of CBDV to ameliorate behavioral abnormalities resembling core and associated symptoms of ASD. At the neurochemical level, symptomatic CBDV restores hippocampal endocannabinoid signaling and neuroinflammation induced by prenatal VPA exposure.

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

“…On behavioral level, our ndings have con rmed that VPA-exposed rats exhibited the core symptoms of ASD, impaired social interaction and repetitive behavior, possibly co-occurred emotional and cognitive problems. Meanwhile, what we found that prenatal VPA exposure inducing similar disturbance of eCB system in offspring rats to ASD children was in accordance with prior researches [16,18], which indicating a reduced eCB tone in ASD. Therefore, we evaluated e cacy of boosting 2-AG levels by hydrolysis inhibitor JZL184 toward repetitive and stereotypical behaviors, hyperactivity, de cits in social and cognitive functioning in VPA-induced rats.…”

“…Interestingly, in Siniscalco's study, FAAH mRNA expression did not signi cantly change and NAPE-PLD slightly decreased in 17 ASD cases and 22 healthy controls [13]. Our ndings from animals were in keeping with previous reports that upregulated expression of FAAH and MAGL in VPA-induced rats [18,44]. As a whole, our results and other studies highlighted the presence of a reduced eCB signaling in ASD children and animal model that might be responsible for the de cits in the cognitive and social domain.…”

“…In addition, several lines of work pointed out that eCB changes appeared to be region-speci c, so we did not observe similar pro le and magnitude of eCBs in the hippocampus and in the PFC. In line with that changes of eCB system are more pronounced in the hippocampus with respect to the PFC [18].…”

“…Siniscalco [13] showed similar results to ours, they found unchanged CB1 mRNA levels and upregulated CB2R mRNA and protein levels in ASD-PBMCs as compared to healthy subjects. That prenatal VPA exposure increased CB1R protein levels were also observed in Zamberletti study [18]. Remarkably, CB1R and CB2R activation exert diverse consequences across cellular physiology.…”

“…In VPA-induced rats, well-known environmental-based model, there was a reduction in MAGL expression and unaltered levels of AEA, PEA, OEA and 2-AG [16]. Melancia [17] showed CB1R activation decreased, while Zamberletti [18] found CB1R upregulated. BTBR, an inbred mouse strain known to model of idiopathic autism, showed higher CB1R density [19].…”