On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence

Paredes-Ruiz, Karen Jaqueline; Chavira-Ramos, Karla; Orozco‐Morales, Mario; Karasu, Çi̇men; Tinkov, Alexey A.; Aschner, Michael; Santamarı́a, Abel; Colín-González, Ana Laura

doi:10.1007/s12640-021-00424-z

Cited by 4 publications

(6 citation statements)

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“…A thorough understanding of the consequences of functional alterations in the eCB system is critical, as targeting CB receptors, inhibiting eCBs uptake and/or blocking their degradation are promising therapeutic approaches to treat eye diseases [40,41] as well as other CNS conditions such as Parkinson's and Huntington's disease [42,43], with several clinical trials underway (for review see [44]). The phytocannabinoids THC and cannabidiol (CBD) have been shown to be neuroprotective in experimental animal models of diabetic retinopathy and glaucoma [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Tonic Endocannabinoid Levels Modulate Retinal Signaling

Yates

Huang

Protti

2022

IJERPH

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The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.

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Section: Discussionmentioning

confidence: 99%

Tonic Endocannabinoid Levels Modulate Retinal Signaling

Yates

Huang

Protti

2022

IJERPH

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“…In pre-clinical and clinical studies an indirect approach to increase eCBs has predominated due to the unwanted biphasic and psychoactive effects of targeting CB1r directly with (high potency) THC. We direct the reader to an excellent recent review on the pre-clinically and clinically observed effects of indirectly acting cannabinoid drugs ( Paredes-Ruiz et al, 2021 ). In the remainder of this section, we will briefly discuss the most recent findings on the most widely used agents.…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

“…Compounds that inhibit the 2-AG degrading enzyme, MAGL, effectively increase levels of 2-AG while FAAH-inhibitors increase endogenous levels of AEA. A commonly used FAAH-inhibitor, URB597, has been shown to improve inflammatory and pain conditions in several models of neurodegeneration, as well as a wide variety of central nervous system disorders that include stress, migrane and depression ( Paredes-Ruiz et al, 2021 ). However, URB597 has also been reported to have no effect on indices of inflammation and cognitive deficit as measured by the Morris water maze test in 5xFAD mice ( Vazquez et al, 2015 ).…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

“…While FAAH inhibitors have potentially broad ranging applications, MAGL inhibitors are thought to be more relevant for inflammatory conditions. One of the most studied MAGL inhibitors, JZL184, has been shown to decrease the reactivity of glial cells while concurrently reducing the production of pro-inflammatory mediators in several models in neurodegenerative disease, though none immediately pertinent to AD ( Paredes-Ruiz et al, 2021 ).…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

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Targeting the cannabinoid system to counteract the deleterious effects of stress in Alzheimer’s disease

Shade

Ross

Bockstaele

2022

Front. Aging Neurosci.

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Alzheimer’s disease is a progressive neurodegenerative disorder characterized histologically in postmortem human brains by the presence of dense protein accumulations known as amyloid plaques and tau tangles. Plaques and tangles develop over decades of aberrant protein processing, post-translational modification, and misfolding throughout an individual’s lifetime. We present a foundation of evidence from the literature that suggests chronic stress is associated with increased disease severity in Alzheimer’s patient populations. Taken together with preclinical evidence that chronic stress signaling can precipitate cellular distress, we argue that chronic psychological stress renders select circuits more vulnerable to amyloid- and tau- related abnormalities. We discuss the ongoing investigation of systemic and cellular processes that maintain the integrity of protein homeostasis in health and in degenerative conditions such as Alzheimer’s disease that have revealed multiple potential therapeutic avenues. For example, the endogenous cannabinoid system traverses the central and peripheral neural systems while simultaneously exerting anti-inflammatory influence over the immune response in the brain and throughout the body. Moreover, the cannabinoid system converges on several stress-integrative neuronal circuits and critical regions of the hypothalamic-pituitary-adrenal axis, with the capacity to dampen responses to psychological and cellular stress. Targeting the cannabinoid system by influencing endogenous processes or exogenously stimulating cannabinoid receptors with natural or synthetic cannabis compounds has been identified as a promising route for Alzheimer’s Disease intervention. We build on our foundational framework focusing on the significance of chronic psychological and cellular stress on the development of Alzheimer’s neuropathology by integrating literature on cannabinoid function and dysfunction within Alzheimer’s Disease and conclude with remarks on optimal strategies for treatment potential.

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“…To transfer knowledge about the physiology and pathophysiology of the endocannabinoidome (of vertebrates, including humans) into possible therapeutic use, intensive preclinical and clinical research studies are underway (see below). Experimental preclinical research, together with clinical trials (i.e., translational research), is focused in geriatrics on the validation of therapeutic approaches using either certain cannabinoids [5][6][7][8][9] or agents enhancing endocannabinoid activities without binding to cannabinoid receptors (e.g., endocannabinoid biodegradation inhibitors) [10,11].…”

Section: Introductionmentioning

confidence: 99%

The Main Therapeutic Applications of Cannabidiol (CBD) and Its Potential Effects on Aging with Respect to Alzheimer’s Disease

Trojan,

Landa,

Šulcová

et al. 2023

Biomolecules

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The use of cannabinoids (substances contained specifically in hemp plants) for therapeutic purposes has received increased attention in recent years. Presently, attention is paid to two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). With respect to the psychotropic effects and dependence potential of THC (though it is very mild), its use is associated with certain restrictions, and thus the therapeutic properties of CBD are frequently emphasized because there are no limitations associated with the risk of dependence. Therefore, this review covers the main pharmacodynamic and pharmacokinetic features of CBD (including characteristics of endocannabinoidome) with respect to its possible beneficial effects on selected diseases in clinical practice. A substantial part of the text deals with the main effects of CBD on aging, including Alzheimer’s disease and related underlying mechanisms.

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On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence

Cited by 4 publications

References 320 publications

Tonic Endocannabinoid Levels Modulate Retinal Signaling

Tonic Endocannabinoid Levels Modulate Retinal Signaling

Targeting the cannabinoid system to counteract the deleterious effects of stress in Alzheimer’s disease

The Main Therapeutic Applications of Cannabidiol (CBD) and Its Potential Effects on Aging with Respect to Alzheimer’s Disease

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