Circadian Regulation of IOP Rhythm by Dual Pathways of Glucocorticoids and the Sympathetic Nervous System

Abstract

PURPOSE. Elevated IOP can cause the development of glaucoma. The circadian rhythm of IOP depends on the dynamics of the aqueous humor and is synchronized with the circadian rhythm pacemaker, that is, the suprachiasmatic nucleus. The suprachiasmatic nucleus resets peripheral clocks via sympathetic nerves or adrenal glucocorticoids. However, the detailed mechanisms underlying IOP rhythmicity remain unclear. The purpose of this study was to verify this regulatory pathway. METHODS. Adrenalectomy and/or superior cervical ganglionectomy were performed in C57BL/6J mice. Their IOP rhythms were measured under light/dark cycle and constant dark conditions. Ocular administration of corticosterone or norepinephrine was also performed. Localization of adrenergic receptors, glucocorticoid receptors, and clock proteins Bmal1 and Per1 were analyzed using immunohistochemistry. Period2::luciferase rhythms in the cultured iris/ciliary bodies of adrenalectomized and/or superior cervical ganglionectomized mice were monitored to evaluate the effect of the procedures on the local clock. The IOP rhythm of retina and ciliary epithelium-specific Bmal1 knockout mice were measured to determine the significance of the local clock. RESULTS. Adrenalectomy and superior cervical ganglionectomy disrupted IOP rhythms and the circadian clock in the iris/ciliary body cultures. Instillation of corticosterone and norepinephrine restored the IOP rhythm. β2-Adrenergic receptors, glucocorticoid receptors, and clock proteins were strongly expressed within the nonpigmented epithelia of the ciliary body. However, tissue-specific Bmal1 knockout mice maintained their IOP rhythm. CONCLUSIONS. These findings suggest direct driving of the IOP rhythm by the suprachiasmatic nucleus, via the dual corticosterone and norepinephrine pathway, but not the ciliary clock, which may be useful for chronotherapy of glaucoma.

Involvement of trabecular meshwork phagocytic suppression by sympathetic norepinephrine in nocturnal intraocular pressure rise

“…This regulatory pathway is consistent with β1-AR-mediated circadian regulation of the pineal gland 58 . In our previous report, NE instillation generated a transient IOP increase within 1 day, but not the day after instillation 19 . It may be possible to partly explain not only the AH production rhythm, but also the NEmediated driven-out rhythm of AH out ow resistance.…”

“…Drug instillation was performed as described in our previous report 19 . Unanesthetized 8-week old male mice were used in this study.…”

“…Although adrenalectomy (ADX) reportedly dampens the IOP rhythms in mice under a light/dark cycle 17 , the circadian aqueous-ow pattern is normal in human patients after surgical ADX 18 . These contradictory effects of NE and glucocorticoids (GCs) may explain the recent discovery demonstrating the dual pathway by which both NE and GCs transmit timing information to the eye to form the IOP rhythm in mice 19 . However, the detailed molecular mechanism remains unclear.…”

Seasonal variations and climatic factors on acute primary angle‐closure admission in southern China: a 5‐year hospital‐based retrospective study

“…In addition, sympathetic nerve activity increases with an increase in core temperature in response to acute heat stress (Niimi et al 1997). Norepinephrine released by the sympathetic nerve could be involved in mediating IOP rhythm (Ikegami et al 2020). As the lens thickness increases with age, the lens is thicker in elderly individuals than in younger individuals (Zeng et al 2012).…”

Altered circadian rhythms and sleep in a new Angelman Syndrome mouse model

“…To rule out the possibility that this altered behavior was caused by stress or anxiety, we measured stress hormones and neurotransmitters in the serum and brain during the day phase of LD. Corticosterone and norepinephrine release are regulated by stress and the circadian clock [Le Minh et al, 2001;Ikegami et al, 2020]. In Ud6-m-/p+ mice, we found that serum corticosterone levels are lower at ZT10-12 (Fig.…”