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The Neuropeptide Alpha-Melanocyte–stimulating Hormone Prevents Persistent Corneal Edema After Injury

Key findings

  • No pharmacologic intervention is currently available for restoring endothelial function after ocular injury
  • Corneal endothelial cells express receptors for neuropeptides, including α-melanocyte–stimulating hormone (α-MSH), which enhances antioxidative response and suppresses apoptosis, among other functions
  • This study investigated the effects of local α-MSH administration on persistent corneal edema and endothelial regeneration in a mouse model of injury-induced endothelial decompensation
  • Treatment with α-MSH mitigated loss of corneal endothelial cells during the critical acute phase of injury and reduced corneal infiltration of neutrophils and macrophages after injury

Loss of corneal endothelial cells (CEnCs) is common after ocular injury and is typically not detectable until severe corneal edema develops and results in decreased vision. CEnCs have limited regenerative capacity, and their loss or dysfunction can lead to persistent corneal edema and loss of corneal clarity.

Agents currently available to prevent corneal edema after eye injury—topical hypertonic saline and topical anti-inflammatory medications—are not very effective and don't prevent CEnC decompensation; they are used primarily to delay (but not treat) corneal swelling. Corneal transplantation is the only established therapy for restoring endothelial function.

Researchers at Mass Eye and Ear recently demonstrated that a neuropeptide can promote endothelial regeneration in vivo during the critical window between ocular injury and the onset of endothelial decompensation. They report their results in The American Journal of Pathology.

The authors are Reza Dana, MD, MSc, MPH, director of the Cornea Service, Jia Yin, MD, PhD, MPH, director of the Cornea Fellowship, Ula V. Jurkunas, MD, associate director of the Cornea Service, and colleagues.


Ocular injuries, including intraocular procedures such as cataract surgery, can disrupt CEnC function in two ways:

  • Directly, by inducing cell death through mechanical injury to the cells or inducing stress that leads to cell death
  • Indirectly, by upregulating proinflammatory cytokines and reactive oxygen species that induce CEnC apoptosis

Apoptotic CEnC loss occurs through intrinsic and extrinsic pathways. The intrinsic pathway is triggered by various signals immediately after injury. Delayed apoptosis (approximately 48 hours after injury) is mediated by alarmin molecules released from dead or damaged corneal cells and proinflammatory molecules secreted by immune cells infiltrating injured corneal tissue.

CEnCs lack direct innervation, but they seem to be supported by nerves. The cells express receptors for a multitude of neuropeptides, principally α-melanocyte–stimulating hormone (α-MSH), whose functions include enhancing antioxidative response, potentiating DNA repair machinery and suppressing apoptosis.

The Mass General team investigated how local administration of α-MSH affected corneal edema and endothelial regeneration in an established mouse model in which ocular injury is produced by cryoablation of the central cornea.

Principal Findings

During the 48 hours after injury, eyes treated with α-MSH showed significantly less CEnC loss, significantly reduced CEnC apoptosis and significantly suppressed neutrophil and macrophage infiltration compared with controls.

Even without any therapeutic intervention, the central corneal endothelial lesion was repopulated within a week by CEnCs derived from uninjured peripheral CEnCs. However, α-MSH–treated mice showed significantly greater CEnC proliferation and significantly faster corneal endothelial wound closure.

In both the treated and control groups there was delayed onset of edema after closure. This indicates impaired functional differentiation of CEnCs in the subacute phase of endothelial injury. Still, α-MSH promoted the differentiation and function of newly generated CEnCs.

Toward Clinical Translation

α-MSH has the potential to be useful in reducing the risk of corneal endothelial decompensation after injury. It will be worthwhile to investigate whether it can also enhance the functional reserve of the corneal endothelium in interventions such as cataract extraction or degenerative conditions of the cornea that also lead to CEnC loss over time.

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Researchers at Mass Eye and Ear have differentiated the cytoprotective action of alpha-melanocyte–stimulating hormone (alpha-MSH) on corneal graft tissue from its effect on the graft recipient's immune response by alternating use of transgenic mice with a truncated alpha-MSH receptor as the graft donor or host.