A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals

Pinelli, Roberto; Biagioni, Francesca; Limanaqi, Fiona; Bertelli, M. S. M.; Scaffidi, Elena; Polzella, Maico; Busceti, Carla Letizia

doi:10.3390/ijms21155563

Cited by 9 publications

(16 citation statements)

References 225 publications

(434 reference statements)

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“…The powerful plastic effects of light are evident already in the retina itself since pioneer papers during the mid'70s up to recent reports. This concept, is well established concerning intrinsic retinal circuitries connected with vision (Berry, 1976;Rose, 1977), and during retinal degeneration (Pinelli et al, 2020a;Pinelli et al, 2021a;2021b;2021c;Strettoi et al, 2022) including plastic changes in the retinal pigment epithelium (Pinelli et al, 2020b). This is now strengthened by evidence showing that specific wavelengths increase proliferation rate of retinal stem cells over four-fold compared with that measured in baseline conditions (Wang et al, 2019).…”

Section: Discussionmentioning

confidence: 87%

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Pinelli¹,

Berti²,

Scaffidi³

et al. 2022

Archives Italiennes De Biologie

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The present manuscript stems from evidence, which indicates that specific wavelength produce an activation of the autophagy pathway in the retina. These effects were recently reported to synergize with the autophagy-inducing properties of specific phytochemicals. The combined administration of photo-modulation and phytochemicals was recently shown to have a strong potential in eliciting the recovery in the course of retinal degeneration and it was suggested as a non-invasive approach named "Lugano protocol" to treat age-related macular degeneration (AMD). Recent translational findings indicate that the protective role of autophagy may extend also to acute neuronal injuries including traumatic neuronal damage. At the same time, very recent investigations indicate that autophagy activation and retinal anatomical recovery may benefit from sound exposure. Therefore, in the present study, the anatomical rescue of a traumatic neuronal loss at macular level was investigated in a patient with idiopathic macular hole by using a combined approach of physical and chemical non-invasive treatments. In detail, light exposure was administered in combination with sound pulses to the affected retina. This treatment was supplemented by phytochemicals known to act as autophagy inducers, which were administered orally for 6 months. This combined administration of light and sound with nutraceuticals reported here as Advanced Lugano's Protocol (ALP) produced a remarkable effect in the anatomical architecture of the retina affected by the macular hole. The anatomical recovery was almost complete at roughly one year after diagnosis and beginning of treatment. The structural healing of the macular hole was concomitant with a strong improvement of visual acuity and the disappearance of metamorphopsia. The present findings are discussed in the light of a synergism shown at neuronal level between light and sound in the presence of phytochemicals to stimulate autophagy and promote proliferation and neuronal differentiation of retinal stem cells.

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Section: Discussionmentioning

confidence: 87%

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Pinelli¹,

Berti²,

Scaffidi³

et al. 2022

Archives Italiennes De Biologie

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“…This may lead to autophagy inhibition concomitantly in the inner choroid and outer retina. Autophagy inhibition is known to promote neovascularization starting from CC under the effects of inflammasome activation within macrophages, which can be induced by Interleukin-1beta (IL-1β), IL-6 and nitrite oxide [39,40]. This is why, in baseline conditions, mTOR dependent autophagy activity in the CC is crucial to modulate the permeability for specific molecules, which may or may not cross the CC to reach the outer retina.…”

Section: Interdependency Of Various Targets Of Autophagy Within Rpe A...mentioning

confidence: 99%

“…Here, proteins are prone to bind sugars to produce advanced glycation end products (AGEs) and lipids, in order to generate lipofuscin [33,[47][48][49], which may further bind melanosomes to form lipo-melano-fuscin [50]. These structures, including mitochondria, represent cellular debris, which produce the building blocks of drusen [40,51]. In fact, these aggregates may be already evident within lysosomes and accumulate in high amounts within the border between RPE and BM [46].…”

Section: A Focus On Rpementioning

confidence: 99%

The Essential Role of Light-Induced Autophagy in the Inner Choroid/Outer Retinal Neurovascular Unit in Baseline Conditions and Degeneration

Pinelli

Ferrucci

Berti

et al. 2023

IJMS

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The present article discusses the role of light in altering autophagy, both within the outer retina (retinal pigment epithelium, RPE, and the outer segment of photoreceptors) and the inner choroid (Bruch’s membrane, BM, endothelial cells and the pericytes of choriocapillaris, CC). Here autophagy is needed to maintain the high metabolic requirements and to provide the specific physiological activity sub-serving the process of vision. Activation or inhibition of autophagy within RPE strongly depends on light exposure and it is concomitant with activation or inhibition of the outer segment of the photoreceptors. This also recruits CC, which provides blood flow and metabolic substrates. Thus, the inner choroid and outer retina are mutually dependent and their activity is orchestrated by light exposure in order to cope with metabolic demand. This is tuned by the autophagy status, which works as a sort of pivot in the cross-talk within the inner choroid/outer retina neurovascular unit. In degenerative conditions, and mostly during age-related macular degeneration (AMD), autophagy dysfunction occurs in this area to induce cell loss and extracellular aggregates. Therefore, a detailed analysis of the autophagy status encompassing CC, RPE and interposed BM is key to understanding the fine anatomy and altered biochemistry which underlie the onset and progression of AMD.

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“…The powerful plastic effects of light are evident already in the retina itself since pioneer papers during the mid'70s up to recent reports. This concept, is well established concerning intrinsic retinal circuitries dedicated to visual perception (Berry, 1976;Rose, 1977), and during retinal degeneration (Pinelli et al, 2020a;Pinelli et al, 2021a;Strettoi et al, 2022) including plastic changes in the retinal pigment epithelium (Pinelli et al, 2020b). This is now strengthened by evidence showing that, specific wavelengths increase proliferation rate of retinal stem cells over four-fold compared with that measured in baseline conditions (Wang et al, 2019).…”

Section: From the Retina To Extra-geniculate Areasmentioning

confidence: 86%

Noradrenergic substrates sensing light within brainstem reticular formation as targets for light-induced behavioral and cardiovascular plasticity

Pinelli¹,

Bucci

Scaffidi³

et al. 2022

Archives Italiennes De Biologie

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The occurrence of pure light exerts a variety of effects in the human body, which span from behavioral alterations, such as light-driven automatic motor activity, cognition and mood to more archaic vegetative functions, which encompass most organs of the body with remarkable effects on the cardiovascular system. Although empirical evidence clearly indicates occurrence of these widespread effects, the anatomical correlates and long-lasting changes within putatively specific neuronal circuitries remain largely unexplored. A specific role is supposed to take place for catecholamine containing neurons in the core of the brainstem reticular formation, which produces a widespread release of noradrenaline in the forebrain while controlling the vegetative nervous system. An indirect as well as a direct (mono-synaptic) retino-brainstem pathway is hypothesized to rise from a subtype of intrinsically photosensitive retinal ganglion cells (iPRGCs), subtype M1, which do stain for Brn3b, and project to the pre-tectal region (including the olivary pre-tectal nucleus). This pathway provides profuse axon collaterals, which spread to the periaqueductal gray and dorsal raphe nuclei. According to this evidence, a retino-reticular monosynaptic system occurs, which powerfully modulate the noradrenergic hub of reticular nuclei in the lateral column of the brainstem reticular formation. These nuclei, which are evidenced in the present study, provide the anatomical basis to induce behavioral and cardiovascular modulation. The occurrence of a highly interconnected network within these nuclei is responsible for light driven plastic effects, which may alter persistently behavior and vegetative functions as the consequence of long-lasting alterations in the environmental light stimulation of the retina. These changes, which occur within the core of an archaic circuitry such as the noradrenaline-containing neurons of the reticular formation, recapitulate, within the CNS, ancestral effects of light-driven changes, which can be detected already within the retina itself at the level of multipotent photic cells.

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A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals

Cited by 9 publications

References 225 publications

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes

The Essential Role of Light-Induced Autophagy in the Inner Choroid/Outer Retinal Neurovascular Unit in Baseline Conditions and Degeneration

Noradrenergic substrates sensing light within brainstem reticular formation as targets for light-induced behavioral and cardiovascular plasticity

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