Biochemical and Biophysical Research Communications
Therapeutic impact of orally administered cannabinoid oil extracts in an experimental autoimmune encephalomyelitis animal model of multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic, incurable disease characterized by inflammation and demyelination in the brain and spinal cord (SC) of the central nervous system (CNS). While the exact mechanism of the disease is unknown, it is widely considered as an autoimmune disease involving the infiltration of inflammatory cells through the blood-brain barrier into the CNS, resulting in the liberation of inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), which are involved in neuropathic pain (NPP) and neuronal destruction [1,2]. MS-induced NPP remains a compelling clinical problem to patients and healthcare providers as it responds poorly to conventional treatments [3].
Anecdotal reports of the beneficial medicinal properties associated with the plant Cannabis Sativa have led to a recent surge in investigative research to explore the potential benefits of cannabinoids that are linked to their ability to modulate the immune system and promote analgesia in chronic pain syndromes such as MS-induced NPP [[4], [5], [6]]. The key cannabinoid components of interest are Δ9-tetrahydrocannabinol (THC) [7], cannabidiol (CBD) and cannabichromene (CBC) [8]. With recent advances in biotechnology, it is possible to consistently adjust the THC/CBD ratios within the plant to achieve the specific desired effect and therapeutic outcomes while minimizing adverse effects [9]. Henceforth, the use of genetically altered plants by certain licensed producers in Canada allows for a tighter control over the consistent reproducibility of the differential production of the three main active constituents: THC, CBD and CBC.
As such, the current research focused on confirming the potential therapeutic efficacy and specific molecular mechanisms by which interventional treatment with cannabinoids exerts their beneficial effects in MS associated NPP syndromes. Our results revealed that significant improvements in neurological assessments of MS induced neurological disability and behavioral assessments of NPP in EAE animals treated with the orally administered cannabinoids. In addition, we investigated the role of cannabinoids on the gene and protein expression of bio-markers, such as TNF-α and BDNF, in a rat EAE model. Moreover, we also determined the pharmacokinetic pattern of cannabinoid oil extracts. This research represents a critical step in scientifically validating the merit for cannabinoid use and sets the foundation for future pilot human clinical trials in patients suffering from MS.
Section snippets
Experimental autoimmune encephalomyelitis (EAE) induction
Adolescent female Lewis rats 9–14 weeks of age (Charles River, Canada) were immunized subcutaneously with 500 μg myelin basic protein gp 69-88 in 1000 μl of Complete Freund's adjuvant at the lower back (0.2 ml/rat) at day 0 (Hooke Laboratories, Cat#. EK-3111, USA). Animals received two intraperitoneal injections of pertussis toxin at days 0 and 2. All animal experiments in this study were conducted according to protocols approved by the University of Manitoba Animal Protocol Management and
Neurological disability score (NDS)
At EAE day 7 neurological deficits began to be displayed in some animals in the form of tail weakness (Fig. 1A). By EAE day 8, all animals started to display clinical signs of neurological disability. Statistical analysis revealed significant decreases in severity of NDS on day 10–13 between EAE cannabinoid (10:10 formulation) treated and EAE untreated groups. In addition, results revealed a 2-day delay in an onset of peak NDS in cannabinoid treated (10:10) EAE animals. Significant decreases
Discussion
Our pre-clinical research findings demonstrate significant improvements in NDS and behavioral assessments of MS induced NPP in EAE animals treated with the orally administered medical grade cannabinoids.
Based on the NDS data, both cannabinoid oral oil formulations (10:10 & 1:20) were able to partially reverse the disease progression after EAE induction as evident by their ability to delay the onset of peak neurological disability and reduce the peak severity. However, the 10:10 cannabinoid
Conflicts of interests
The authors declare no competing interests.
Acknowledgements
The authors gratefully acknowledge the research funding supplied by Prairie Plant Systems Inc. The authors also acknowledge support from Manitoba Multiple Sclerosis Research Network Organization (MMSRNO) for their indirect support provided to this pre-clinical research.
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