Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease
Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal. Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction. Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.
KeywordsCannabinoids Alzheimer’s Neuroprotection Drug discovery Phenotypic screening
Amyloid precursor protein
Drug Enforcement Agency
Cannabidiol 2′,6′ dimethyl ether
Dulbecco’s modified Eagle medium
Familial Alzheimer’s disease
Fetal calf serum
Tetrazolium-based colorimetric assay
Nuclear magnetic resonance
Reactive oxygen species
DS and PM wrote the paper and did most of the screening assays. ZL did the SAR analysis. JG, RD, and KD contributed to some of the screening assays.
This study was supported by grants from the Paul F. Glenn Center for Aging at the Salk Institute (JG), NIH (RO1 AG046153 and RF1 AG054714 to PM and DS, and R41AI104034 to PM), the Edward N. & Della Thome Memorial Foundation (PM), and the Salk Core Facility (NIH-NCI:P30 014195, the Chapman Foundation and the Helmsley Trust).
Compliance with Ethical Standards
Ethics Approval and Consent to Participate
Consent for Publication
Availability of Data and Materials
All of the cell lines used in the screening assays are available. All data generated or analyzed during this study are included in the manuscript or available upon request.
The authors declare that they have no competing interests.
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