Cannabinoid receptors and TRPA1 on neuroprotection in a model of retinal ischemia

Araújo, Daniel Souza Monteiro de; Miya-Coreixas, Vivian Sayuri; Pandolfo, Pablo; Calaza, Karin da Costa

doi:10.1016/j.exer.2016.11.015

Cited by 23 publications

(25 citation statements)

References 60 publications

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“…TRPA1 is suggested to play a role in many different disease states and may be involved in the mediation of the therapeutic effects of cannabinoids (Romano et al, 2013; Araújo et al, 2017). Therefore, more cannabinoids should be tested at this channel in order to better elucidate structure activity relationships.…”

Section: Trpa1mentioning

confidence: 99%

Cannabinoid Ligands Targeting TRP Channels

Muller

Morales

Reggio

2019

Front. Mol. Neurosci.

434

359

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Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be “ionotropic cannabinoid receptors.” Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, N-arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ9-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.

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Section: Trpa1mentioning

confidence: 99%

Cannabinoid Ligands Targeting TRP Channels

Muller

Morales

Reggio

2019

Front. Mol. Neurosci.

434

359

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“…A C C E P T E D ACCEPTED MANUSCRIPT et al, 1999;Yazulla et al, 2000) and ganglion cells (Lalonde et al, 2006;Middleton and Protti, 2011), and neuroprotective actions of cannabinoids have been reported in excitotoxic damage (El-Remessy et al, 2003;Kokona and Thermos, 2015;Opere et al, 2006), ischemia (Araujo et al, 2017;Nucci et al, 2007;Pinar-Sueiro et al, 2013) and glaucoma (Cairns et al, 2016;Nucci et al, 2008;Rapino et al, 2017). In a previous study, we demonstrated that systemic administration of the synthetic cannabinoid HU210 slows retinal neurodegeneration in the P23H rat model of autosomal dominant retinitis pigmentosa (Lax et al, 2014).…”

Section: A N U S C R I P Tmentioning

confidence: 85%

Cannabinoid-mediated retinal rescue correlates with improved circadian parameters in retinal dystrophic rats

Lax

Kutsyr

Esquiva

et al. 2019

Experimental Eye Research

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Ocular pathologies and blindness have been linked to circadian disorders. In previous studies, our group has demonstrated that retinitis pigmentosa is associated with degenerative changes in the melanopsin system and weaker circadian patterns. We have also shown that cannabinoids preserve retinal structure and function in dystrophic P23H rats. This study is consequently aimed at examining whether the morphologic and functional rescue of retinal degeneration by cannabinoids is associated with amelioration of circadian parameters. The synthetic cannabinoid HU210 (100 µg/kg, i.p.) or vehicle were administered to transgenic P23H rats three times per week, from postnatal day 24 to 90. Sprague-Dawley rats were used as a healthy control group. Locomotor activity and scotopic electroretinograms were recorded, and the retinal structure was analyzed at the end of the experiment. The ERG a-and b-wave amplitudes and photoreceptor cell number were more deteriorated in vehicle-administered P23H rats as compared to P23H rats treated with HU210. In cannabinoid-administered P23H rats, the locomotor activity circadian rhythms showed less disturbance than that observed in vehicle-administered P23H rats, the latter showing lower values for mesor, amplitude, acrophase, percentage of variance and non-parametric variables. A positive linear correlation was found between retinal values and circadian parameters of locomotor activity from P23H rats. This study thus provides evidence of a positive correlation between cannabinoid-mediated rescue of retinal structure and function and improvement of circadian rhythmicity.

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“…We previously observed that TRPA1 is expressed in the avascular chick retina, where its pharmacological inhibition attenuated the production of lactate dehydrogenase evoked by oxygen and glucose deprivation, suggesting a protective role 29 . The present data, using genetic deletion of TRPA1, provide evidence for the first time of the essential role of TRPA1 in the damage caused by I/R in the mouse retina, which, like the human retina, is markedly vascularized.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, in a model of sciatic nerve injury, Schwann cell TRPA1 was found to sense the macrophage-dependent oxidative stress burst, sustaining ROS and RCS production and pain signals via an NADPH oxidase 1 (NOX1)-mediated pathway 28 . Recently, we reported that the TRPA1 protein was present in the chick retina 29 , and that pharmacological blockade of this channel attenuated the increase in lactate dehydrogenase, a biomarker of tissue damage evoked by oxygen and glucose deprivation 29 . These findings suggest that TRPA1 may be implicated in retinal injury, but several issues remain to be investigated, including whether TRPA1 is present in the rodent and human retina, and how it participates in the damage cascade evoked by I/R.…”

Section: Introductionmentioning

confidence: 99%

TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice

et al. 2020

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Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wildtype littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.

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Cannabinoid receptors and TRPA1 on neuroprotection in a model of retinal ischemia

Cited by 23 publications

References 60 publications

Cannabinoid Ligands Targeting TRP Channels

Cannabinoid Ligands Targeting TRP Channels

Cannabinoid-mediated retinal rescue correlates with improved circadian parameters in retinal dystrophic rats

TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice

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