Alterations of blood pressure and heart rate circadian rhythmic structure in non-blind patients affected by retinitis pigmentosa

Chronobiology International

Esquiva

Fuentes-Broto

et al. 2016

The melanopsin system consists of intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (mRGCs). These mRGCs mediate several non-image-forming visual functions, including light entrainment of circadian rhythms. Here we evaluate age-related alterations of the melanopsin system and circadian rhythms in P23H line 1 (P23H-1) rats, a rodent model of retinitis pigmentosa (RP). In homozygous P23H-1 rats and wild-type control rats from the same genetic background (Sprague-Dawley), body temperature and locomotor activity were continuously monitored at 10-min intervals for 7 days, once every 4-5 weeks, between 2 and 24 months of age, using a telemetry transmitter. The distribution and number of mRGCs were assessed in control rats at 12, 18, and 24 months of age and in P23H-1 rats aged 12, 18, 24, and 30 months by immunostaining whole-mount retinas with antibodies against melanopsin. The mean density of mRGCs in control rats showed no significant variations when evaluated at 12 and 18 months of age, and fell by approximately 56% between 18 and 24 months of age. Meanwhile, a significant decrease in the mean number of mRGCs was found in 18-month-old P23H-1 rats as compared to 18-month-old control rats (81% decrease). Parametric and non-parametric analyses of the records showed a gradual age-dependent weakening of body temperature and locomotor activity circadian rhythms robustness in both control and P23H-1 rats from 2 to 24 months of age. However, body temperature and locomotor activity circadian patterns were less robust throughout the experiment in P23H-1 as compared to control rats, with lower amplitude, weaker coupling strength to environmental zeitgebers and higher fragmentation of the rhythms. The present study shows that the degeneration of photoreceptors and inner retinal neurons, characteristic of RP, has age-related degenerative effects on the melanopsin system and is associated with weaker circadian patterns.

Section: Discussionmentioning

confidence: 99%

Age-related changes in photosensitive melanopsin-expressing retinal ganglion cells correlate with circadian rhythm impairments in sighted and blind rats

Chronobiology International

Esquiva

Fuentes-Broto

et al. 2016

“…Results of this study provide evidence that retinitis pigmentosa is linked to both a progressive degeneration of retinal structure and function and a gradual deterioration of circadian rhythms, and that chronic administration of cannabinoids is able to rescue both retinal degeneration and circadian disturbances. Previous studies have extensively shown that ocular pathologies are associated with circadian rhythm disturbances (Cugini et al, 2001;Lucas et al, 2003;Lupi et al, 1999;Mrosovsky et al, 1999;Panda et al, 2003;Panda et al, 2002), and our previous studies have demonstrated that melatonin administration partially reverses both vision loss and circadian rhythm fragmentation in dystrophic rats (Lax et al, 2011), but to our knowledge this is the first study to show a positive correlation between rescue of retinal structure and function and improvement of circadian rhythms.…”

Section: Discussionmentioning

confidence: 68%

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

Experimental Eye Research

Kutsyr

Esquiva

et al. 2019

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.

“…Apart from inner retina diseases, circadian dysfunctions have also been reported in advanced stages of diseases affecting the outer retina, such as retinitis pigmentosa [18,27,28,99]. It has been demonstrated that retinal degeneration positively correlates with the occurrence of circadian dysfunctions in P23H line 3 rats [100], an animal model of retinitis pigmentosa (RP), and that advanced stages of the degenerative disease correlate with reduced rhythm amplitudes, weaker coupling strength of the rhythm to environmental zeitgebers, and higher rhythm fragmentation in P23H line 1 rats [63] (Figure 5).…”

Section: Melanopsin-containing Ganglion Cells In Retinal Diseasesmentioning

confidence: 99%

Photosensitive Melanopsin-Containing Retinal Ganglion Cells in Health and Disease: Implications for Circadian Rhythms

Ortuño‐Lizarán

Maneu

et al. 2019

IJMS

Melanopsin-containing retinal ganglion cells (mRGCs) represent a third class of retinal photoreceptors involved in regulating the pupillary light reflex and circadian photoentrainment, among other things. The functional integrity of the circadian system and melanopsin cells is an essential component of well-being and health, being both impaired in aging and disease. Here we review evidence of melanopsin-expressing cell alterations in aging and neurodegenerative diseases and their correlation with the development of circadian rhythm disorders. In healthy humans, the average density of melanopsin-positive cells falls after age 70, accompanied by age-dependent atrophy of dendritic arborization. In addition to aging, inner and outer retinal diseases also involve progressive deterioration and loss of mRGCs that positively correlates with progressive alterations in circadian rhythms. Among others, mRGC number and plexus complexity are impaired in Parkinson’s disease patients; changes that may explain sleep and circadian rhythm disorders in this pathology. The key role of mRGCs in circadian photoentrainment and their loss in age and disease endorse the importance of eye care, even if vision is lost, to preserve melanopsin ganglion cells and their essential functions in the maintenance of an adequate quality of life.