Abstract
Introduction: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive degeneration of upper (UMN) in the primary cortex of the frontal lobe and brainstem, and lower (LMN) motor neurons in the brainstem and spinal cord. There is currently an unmet need for treatment that is effectively able to prevent or treat ALS symptoms and progression. The SOD1G93A (SOD1) transgenic mouse model is currently the most widely used for investigating SOD1 mutations in familial ALS (fALS). These transgenic mice overexpress mutant human SOD1 with a glycine to alanine (Gly93→Ala) substitution at residue 93, and thus exhibit pathological features akin to individuals with familial and some forms of sporadic ALS, providing a valuable tool for research on ALS pathogenesis and preclinical testing of potential therapies. There is increasing evidence that manipulation of the endocannabinoid system (ECS) modulates many of the processes involved in ALS pathology, and as such targeting the ECS may have beneficial disease-modifying potential for ALS. The phytocannabinoid cannabidiol (CBD) is thought to provide immunomodulatory and neuroprotective effects by acting on receptors in the ECS.Aim: The research conducted as part of the current project aims to contribute to the field of medical research pursuing effective treatment for ALS through a preclinical investigation of the behavioural effects of chronic treatment with a medium dose (20 mg/kg) of CBD on motor performance and other behavioural domains in a transgenic mouse model for ALS, SOD1G93A .
Materials and methods: Male and female SOD1 transgenic and wild type-like (WT) control mice were treated daily from postnatal day 93 (PND93) via intraperitoneal (i.p.) injections with 20 mg/kg bodyweight CBD or vehicle control. After 21 days, injections 8 continued, and mice were subjected to a variety of behavioural paradigms in which they were tested for motor function in the pole test, the wirehang test, and the accelerod; locomotion, exploration and anxiety-like behaviours in the open field (OF) test; intermediate-term spatial recognition memory in the Y-maze; sociability in the social interaction (SI) test; Fear-associated learning in the fear conditioning (FC) paradigm; and startle habituation and sensorimotor gating deficits in the prepulse inhibition (PPI) test. Results: SOD1 transgenic mice showed reductions in bodyweight over time, with CBD treatment having a subtle beneficial effect in male transgenic mice. SOD1 mice exhibited motor deficits in the wirehang and accelerod paradigms, falling off the apparatus sooner than their WT littermates. Chronic CBD treatment had no impact on any motor impairments. In the OF arena, SOD1 transgenic males showed reduced locomotion, exploration and increased anxiety-like behaviours, as well as an inability to habituate to the test arena over time. No effects of CBD treatment were detected. SOD1 transgenic females engaged in social interactions for longer than WT females, and no treatment effects were detected. Memory as tested in the Y-maze and FC remained intact across experimental groups, however, CBD treatment had a negative effect on Y-maze performance, reducing novel arm preference in males. Finally, SOD1 transgenic mice exhibited impaired acoustic startle response (ASR) in the PPI test, however no PPI deficits were observed. CBD had no effect on any sensorimotor gating impairments. Summary and conclusion: SOD1 transgenic mice displayed expected motor impairments and particular cognitive deficits indicative of UMN and LMN degeneration. Importantly, treatment with 20 mg/kg bodyweight CBD had no effect on any functional measure tested. Future research should consider different dosing and treatment regimes, multidrug combinations, or alternative therapies.
| Date of Award | 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Tim Karl (Supervisor) & Rossana Rosa Porto (Supervisor) |