Neuroprotection by (endo)Cannabinoids in Glaucoma and Retinal Neurodegenerative Diseases

Rapino, Cinzia; Tortolani, Daniel; Scipioni, Lucia; Maccarrone, Mauro

doi:10.2174/1570159x15666170724104305

Cited by 61 publications

(46 citation statements)

References 149 publications

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“…Long-term oral treatment with CBD for 8 months also prevented deficits of social recognition memory in transgenic AβPPSwe/PS1ΔE9 (AβPP × PS1) mice ( Cheng et al, 2014c ) and using the same model, but treating the animals daily with intraperitoneal injections of CBD for 3 weeks, Cheng et al (2014a) reported that CBD reversed social and novel object recognition deficits without affecting anxiety-related behaviors. In addition, the presently reported ability of AEA to blunt the enlargement of the brain ventricles suggests an indirect preventive action against neuronal death, which is a well-reported neuroprotective feature of endocannabinoids ( Rapino et al, 2017 ; Vrechi et al, 2018 ), including AEA ( Xu et al, 2017 ). Further analysis of specific markers of neurodegeneration such as Fluorojade, caspase-3 and Bax, which are increased by icv-STZ ( Espinosa et al, 2013 ; Song et al, 2014 ; Biswas et al, 2016 ), would be interesting to better understand the mechanisms behind the neuroprotective role of AEA against the ventricle enlargement.…”

Section: Discussionmentioning

confidence: 94%

Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats

et al. 2018

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Alzheimer’s disease (AD) is characterized by multiple cognitive deficits including memory and sensorimotor gating impairments as a result of neuronal and synaptic loss. The endocannabinoid system plays an important role in these deficits but little is known about its influence on the molecular mechanism regarding phosphorylated tau (p-tau) protein accumulation – one of the hallmarks of AD –, and on the density of synaptic proteins. Thus, the aim of this study was to investigate the preventive effects of anandamide (N-arachidonoylethanolamine, AEA) on multiple cognitive deficits and on the levels of synaptic proteins (syntaxin 1, synaptophysin and synaptosomal-associated protein, SNAP-25), cannabinoid receptor type 1 (CB1) and molecules related to p-tau degradation machinery (heat shock protein 70, HSP70), and Bcl2-associated athanogene (BAG2) in an AD-like sporadic dementia model in rats using intracerebroventricular (icv) injection of streptozotocin (STZ). Our hypothesis is that AEA could interact with HSP70, modulating the level of p-tau and synaptic proteins, preventing STZ-induced cognitive impairments. Thirty days after receiving bilateral icv injections of AEA or STZ or both, the cognitive performance of adult male Wistar rats was evaluated in the object recognition test, by the escape latency in the elevated plus maze (EPM), by the tone and context fear conditioning as well as in prepulse inhibition tests. Subsequently, the animals were euthanized and their brains were removed for histological analysis or for protein quantification by Western Blotting. The behavioral results showed that STZ impaired recognition, plus maze and tone fear memories but did not affect contextual fear memory and prepulse inhibition. Moreover, AEA prevented recognition and non-associative emotional memory impairments induced by STZ, but did not influence tone fear conditioning. STZ increased the brain ventricular area and this enlargement was prevented by AEA. Additionally, STZ reduced the levels of p-tau (Ser199/202) and increased p-tau (Ser396), although AEA did not affect these alterations. HSP70 was found diminished only by STZ, while BAG2 levels were decreased by STZ and AEA. Synaptophysin, syntaxin and CB1 receptor levels were reduced by STZ, but only syntaxin was recovered by AEA. Altogether, albeit AEA failed to modify some AD-like neurochemical alterations, it partially prevented STZ-induced cognitive impairments, changes in synaptic markers and ventricle enlargement. This study showed, for the first time, that the administration of an endocannabinoid can prevent AD-like effects induced by STZ, boosting further investigations about the modulation of endocannabinoid levels as a therapeutic approach for AD.

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Section: Discussionmentioning

confidence: 94%

Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats

et al. 2018

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“…These variations make the accurate diagnosis extremely challenging. In clinical settings, no medication can halt the photoreceptor death and visual devastations in RP patients (Khan et al, 2017;Rapino et al, 2018). Accumulating evidences suggest that the oxidative stress contributes to the photoreceptor apoptosis of RP.…”

Section: Introductionmentioning

confidence: 99%

Intravitreal Delivery of Melatonin Is Protective Against the Photoreceptor Loss in Mice: A Potential Therapeutic Strategy for Degenerative Retinopathy

Tian

Yao

et al. 2020

Front. Pharmacol.

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Melatonin is a circadian hormone with potent cytoprotective effects. Retinitis pigmentosa (RP) comprises a heterogeneous group of inherent retinopathies that characterized by the photoreceptor death in bilateral eyes. The N-methyl-N-nitrosourea (MNU) administered mouse is a type of chemically induced RP model with rapid progressive rate. We intend to study the melatonin mediated effects on the MNU administered mice. Melatonin was delivered into the vitreous body of the MNU administered mice. Subsequently, the melatonin treated mice were subjected to histological analysis, optokinetic behavior tests, spectral-domain optical coherence tomography (SD-OCT), and electroretinogram (ERG) examination. Multi-electrodes array (MEA) was used to analyze the status of visual signal transmission within retinal circuits. Biochemical analysis was performed to quantify the expression levels of antioxidative enzymes, oxidative stress markers, and apoptotic factors in the retinas. The intravitreal injection of melatonin ameliorated effectively the MNU induced photoreceptor degeneration. Melatonin therapy mitigated the spontaneous firing response, and preserved the basic configurations of visual signal pathway in MNU administered mice. MEA is effective to evaluate the pharmacological effects on retina. Of note, the cone photoreceptors in degenerative retinas were rescued efficiently by melatonin therapy. Melatonin afforded these protective effects by modulating the apoptotic cascades and alleviating the oxidative stress. These findings suggest that melatonin could act as an alternative treatment for degenerative retinopathy. Melatonin Frontiers in Pharmacology | www.frontiersin.org

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“…It is known that activation of cannabinoid receptors decreases aqueous humor production and increases trabecular and uveoscleral outflow, thereby reducing intraocular pressure (IOP) . Recent studies suggest that activation of cannabinoid receptor may feature IOP independent effects, such as neuroprotective properties or improvement in ocular hemodynamics . In particular, the finding that activation of cannabinoid receptors show vasoactive actions in isolated perfused retinal arterioles makes it an interesting target to alter ocular blood flow independent of IOP …”

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confidence: 99%

The Effect of Orally Administered Dronabinol on Optic Nerve Head Blood Flow in Healthy Subjects—A Randomized Clinical Trial

Hommer

Kallab

Szegedi

et al. 2020

Clin Pharma and Therapeutics

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It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics. The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects. The study was carried out in a randomized, placebo‐controlled, double‐masked, two‐way crossover design in 24 healthy subjects. For each study participant, 2 study days were scheduled, on which they either received capsules containing 5 mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for 6 minutes to increase mean arterial blood pressure (MAP). This was repeated 1 hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP–IOP. Dronabinol was well tolerated and no cannabinoid‐related psychoactive effects were reported. Neither administration of dronabinol nor placebo had an effect on IOP, MAP, or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5 ± 8.1%, whereas placebo did not show a change in ONHBF (0.3 ± 7.4% vs. baseline, P < 0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise. In conclusion, the present data indicate that low‐dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP, or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in patients with glaucoma.

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Neuroprotection by (endo)Cannabinoids in Glaucoma and Retinal Neurodegenerative Diseases

Cited by 61 publications

References 149 publications

Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats

Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats

Intravitreal Delivery of Melatonin Is Protective Against the Photoreceptor Loss in Mice: A Potential Therapeutic Strategy for Degenerative Retinopathy

The Effect of Orally Administered Dronabinol on Optic Nerve Head Blood Flow in Healthy Subjects—A Randomized Clinical Trial

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