Attenuation of Oxidative Stress by Cannabinoids and Cannabis Extracts in Differentiated Neuronal Cells

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Abstract

In this proof-of-concept study, the antioxidant activity of phytocannabinoids, namely cannabidiol (CBD) and Δ9- tetrahydrocannabinol (THC), were investigated using an in vitro system of differentiated human neuronal SY-SH5Y cells. The oxidative stress was induced by hydrogen peroxide, as reactive oxygen species (ROS). Alzheimer’s disease (AD)-like pathological conditions were mimicked in vitro by treating the differentiated neuronal cells with amyloid-β _1–42 (Aβ _1–42) in the presence of Cu(II). We showed that THC had a high potency to combat oxidative stress in both in vitro models, while CBD did not show a remarkable antioxidant activity. The cannabis extracts also exhibited a significant antioxidant activity, which depended on the ratio of the THC and CBD. However, our results did not suggest any antagonist effect of the CBD on the antioxidant activity of THC. The effect of cannabis extracts on the cell viability of differentiated human neuronal SY-SH5Y cells was also investigated, which emphasized the differences between the bioactivity of cannabis extracts due to their composition. Our preliminary results demonstrated that cannabis extracts and phytocannabinoids have a promising potential as antioxidants, which can be further investigated to develop novel pharmaceuticals targeting oxidative stress therapy.

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The amyloid hypothesis of Alzheimer's disease at 25 years

Dennis Selkoe, John Hardy (2016)

Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

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Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

C. Cheignon, M. Tomás, D Bonnefont-Rousselot … (2017)

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

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Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options

Bayani Uttara, Ajay V. Singh, Paolo Zamboni … (2009)

Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to serious penalty leading to neuro-degeneration. Neural cells suffer functional or sensory loss in neurodegenerative diseases. Apart from several other environmental or genetic factors, oxidative stress (OS) leading to free radical attack on neural cells contributes calamitous role to neuro-degeneration. Though, oxygen is imperative for life, imbalanced metabolism and excess reactive oxygen species (ROS) generation end into a range of disorders such as Alzheimer’s disease, Parkinson’s disease, aging and many other neural disorders. Toxicity of free radicals contributes to proteins and DNA injury, inflammation, tissue damage and subsequent cellular apoptosis. Antioxidants are now being looked upon as persuasive therapeutic against solemn neuronal loss, as they have capability to combat by neutralizing free radicals. Diet is major source of antioxidants, as well as medicinal herbs are catching attention to be commercial source of antioxidants at present. Recognition of upstream and downstream antioxidant therapy to oxidative stress has been proved an effective tool in alteration of any neuronal damage as well as free radical scavenging. Antioxidants have a wide scope to sequester metal ions involved in neuronal plaque formation to prevent oxidative stress. In addition, antioxidant therapy is vital in scavenging free radicals and ROS preventing neuronal degeneration in post-oxidative stress scenario.

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Journal

Journal ID (nlm-ta): Pharmaceuticals (Basel)

Journal ID (iso-abbrev): Pharmaceuticals (Basel)

Journal ID (publisher-id): pharmaceuticals

Title: Pharmaceuticals

Publisher: MDPI

ISSN (Electronic): 1424-8247

Publication date (Electronic): 22 October 2020

Publication date Collection: November 2020

Volume: 13

Issue: 11

Electronic Location Identifier: 328

Affiliations

[1 ]Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada; aruna.raja@ 123456utoronto.ca (A.R.); soha.ahmadi@ 123456mail.utoronto.ca (S.A.)

[2 ]Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada

[3 ]Lupos Biotechnology Inc., 221 Morrish Road, Toronto, ON M1C 1E9, Canada; fernanda.decosta@ 123456lupos.ca (F.d.C.); nan.li@ 123456lupos.ca (N.L.)

Author notes

[* ]Correspondence: kagan.kerman@ 123456utoronto.ca

[†]

These authors contributed equally to this work.

Author information

Soha Ahmadi https://orcid.org/0000-0002-7182-9049

Fernanda de Costa https://orcid.org/0000-0002-3321-3921

Kagan Kerman https://orcid.org/0000-0003-3511-8570

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Publisher ID: pharmaceuticals-13-00328

DOI: 10.3390/ph13110328

PMC ID: 7690570

PubMed ID: 33105840

SO-VID: eddb8bb9-10d1-469b-a275-24a2513f0514

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Attenuation of Oxidative Stress by Cannabinoids and Cannabis Extracts in Differentiated Neuronal Cells

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Most cited references 71

The amyloid hypothesis of Alzheimer's disease at 25 years

Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options

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