Ghimire Sandip, Kreilaus Fabian, Rosa Porto Rossana, Anderson Lyndsey L, Yerbury Justin J, Arnold Jonathon C, Karl Tim
School of Medicine, Western Sydney University, Campbelltown, NSW, 2560, Australia.
Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
Psychopharmacology (Berl). 2025 Apr 14. doi: 10.1007/s00213-025-06785-z.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1).
Male and female SOD1 and wild type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.
CBD treatment ameliorated the bodyweight loss in female SOD1 mice, tended to reinstate sociability in SOD1 males, strengthened social recognition memory in SOD1 females, and improved the PPI response in younger SOD1 females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1 mice and decreased the acoustic startle response and strengthened cue freezing in male mice.
Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1 mice in a sex specific manner without altering the motor phenotype.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，在疾病后期会影响自主肌肉运动以及认知和其他行为领域。目前尚无针对ALS的有效治疗方法。ALS中明显存在神经炎症加剧、氧化应激以及内源性大麻素系统改变。植物大麻素大麻二酚（CBD）具有抗炎和抗氧化特性。因此，我们评估了慢性口服大麻二酚（CBD）治疗对携带G93A突变（SOD1）的肌萎缩侧索硬化症铜锌超氧化物歧化酶1（SOD1）小鼠模型中与ALS相关行为领域的治疗效果。
从10周龄开始，给雄性和雌性SOD1及野生型样（WT）同窝小鼠喂食对照（CHOW）或富含CBD的饲料（相当于每天36 mg/kg的剂量）。从11周龄到19周每周记录体重和运动表现，并在12周和18周记录旷场行为。还对小鼠进行了前脉冲抑制（PPI）、社交行为以及恐惧相关记忆测试。
CBD治疗改善了雌性SOD1小鼠的体重减轻，倾向于恢复SOD1雄性小鼠的社交能力，增强了SOD1雌性小鼠的社会识别记忆，并在较高前脉冲强度下改善了年轻SOD1雌性小鼠的PPI反应。CBD对运动障碍没有影响，但反而逆转了12周龄雄性SOD1小鼠的抗焦虑样表型，降低了雄性小鼠的听觉惊吓反应并增强了线索冻结反应。
因此，当前的CBD口服治疗剂量延缓了雄性和雌性小鼠的疾病进展（通过体重推断），并以性别特异性方式改善了SOD1小鼠的特定认知缺陷，而未改变运动表型。
