Avaliação dos Efeitos Neuroprotetores dos Canabinoides Presentes no Óleo Integral de Cannabis sativa Sobre os Prejuízos Relacionados à Memória em Camundongas C57BL/6 Submetidas a Protocolos de Estresse Crônico

Abstract

Chronic stress is a prevalent condition in contemporary society and represents an important risk factor for cognitive deficits, particularly memory impairments, mediated by dysfunctions of the hypothalamic–pituitary–adrenal axis, oxidative stress, and neuroinflammation. Despite the widespread use of animal models to investigate its pathophysiological mechanisms, most studies focus on males, disregarding the hormonal fluctuations of the estrous cycle in females. In this context, phytocannabinoids from Cannabis sativa have been investigated for their potential neuromodulatory, antioxidant, and anti-inflammatory effects. This study evaluated the effects of whole spectrum Cannabis sativa oil (CFS) on the spatial memory of C57BL/6 female mice subjected to moderate chronic stress, considering the estrous cycle. Animals (n=29) were distributed into five groups: (G0) stress + saline; (G1) control + olive oil; (G2) stress + olive oil; (G3) control + CFS; and (G4) stress + CFS. The moderate stress protocol consisted of 14 days of movement restriction (2h/day) combined with predator-prey exposure (1h/day). Memory was assessed in the Morris Water Maze (MWM), considering escape latency (acquisition) and time spent in the target quadrant (retention), and the estrous cycle was monitored by vaginal cytology. The results showed that the stressed groups (G0, G2, and G4) did not present memory deficits, suggesting resilience to the protocol. However, females treated with CFS under basal conditions (G3) exhibited impaired memory acquisition, whereas the stress + CFS group (G4) maintained performance, indicating a possible biphasic effect of the oil. Estrous cycle analysis indicated longer escape latency in diestrus; however, no consistent conclusions could be drawn. In conclusion, females were resilient to chronic stress, and CFS may impair spatial memory under basal conditions, possibly due to the presence of Δ9-THC, but not after stress exposure, suggesting a context-dependent action. These findings highlight the importance of considering sex and hormonal status in preclinical studies on stress and memory.