Connexin43 Mimetic Peptide Improves Retinal Function and Reduces Inflammation in a Light-Damaged Albino Rat Model

Abstract

PURPOSE. Drugs that regulate connexin43 (Cx43) gap junction channels can reduce the spread of injury and improve functional outcomes after nervous system trauma. In the eye, Cx43 expression increases in the choroid following light damage. The aim of this study was to investigate whether Cx43 hemichannel block could preserve retinal function postinjury. RESULTS. Light-damaged rat eyes had (1) reduced neuronal responses in both the rod and cone pathways and (2) marked inflammatory responses in the choroid and retina. Peptide5 significantly preserved function of photoreceptoral and postphotoreceptoral neurons in these animals. This was evident 24 hours after injury and 2 weeks later, as shown by improved mixed a-wave and mixed b-wave amplitudes, isolated rod PII and PIII amplitudes, and cone PII responses when compared with sham-treated controls. Retinal thinning and inflammation were also significantly reduced in Peptide5-treated eyes when compared with sham-treated controls.CONCLUSIONS. Blocking Cx43 hemichannels after light damage can significantly improve functional outcomes of neurons in both the rod and cone photo-transduction pathways in the light-damaged animal model, likely by reducing choroid inflammation and suppressing the glial-mediated inflammatory response. These data may have relevance for the treatment of conditions such as diabetic retinopathy and age-related macular degeneration.

Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage

“…4 According to recent reports, the inflammatory reaction is associated with an increase in connexin43 (Cx43) expression, primarily in the choroid, RPE, and retina. 5 Cx43 forms gap junctions that play a major role in the bidirectional movement of ions and metabolites between cells, contributing to the blood-retinal barrier in endothelial cells. [6][7][8][9][10] However, Cx43 also forms hemichannels in the plasma membrane, including that of endothelial cells and astrocytes in response to injury, and these ''pathological pores'' play a major role in the inflammatory reaction and its perpetuation.…”

“…[11][12][13][14][15][16][17] This has been demonstrated in experiments in which connexin channel-blocking mimetic peptides have been used to prevent connexin hemichannel opening and reduce the inflammatory response. 5,[18][19][20][21][22][23][24][25] However, the short half-life of native Cx43 mimetic peptides 26 in solution is potentially an obstacle for long-term therapeutic effects.…”

“…21,35,36 We have previously shown that a double injection of unmodified Cx43MP is protective against damage in the intense light-exposed rat retina. 5 In this study we investigated the effect of sustained Cx43MP delivery from NPs and monitored the effect on inflammation, as well as connexin expression that occurs in the light-damaged rat retina.…”

“…The results of ERG signals were amplified 1000 times by a Dual Bio Amp (AD Instruments, NSW, Australia), and waveforms were recorded by using the Scope software (AD Instruments, Dunedin, New Zealand) and analyzed using published algorithms of the amplitudes of a-wave and b-wave. 5,45 Optical Coherence Tomography…”

Connexin channel and its role in diabetic retinopathy

“…Blocking Cx43 hemichannels by this mimetic peptide reduces vascular leakage and increases retinal ganglion cell survival after ischemic injury. In another study, Peptide5 is similarly delivered via intraperitoneal injection in albino rat model and this treatment reduces neuronal damages likely by reducing choroid inflammation caused by light damage (Guo et al, 2016). The approaches for new peptide drug formulation and delivery are reported in two papers; in the first paper, Cx43 mimetic peptides are encapsulated into slow-release poly(lactic-co-glycolic) acid nanoparticles and microparticles and a triphasic release is shown in vitro with an initial burst release and following a slow release (Chen et al, 2015b).…”