Brimonidine Enhances the Electrophysiological Response of Retinal Ganglion Cells through the Trk-MAPK/ERK and PI3K Pathways in Axotomized Eyes.
To investigate changes in retinal ganglion cell (RGC) activity by measuring the positive scotopic threshold response (pSTR) of the electroretinogram (ERG) in axotomized eyes after brimonidine injection.



In 50 adult Sprague-Dawley rats, the left eye was axotomized and injected with phosphate buffered saline (PBS) or brimonidine and the contralateral right eye was left untreated. Scotopic ERGs were recorded simultaneously from both eyes on days 1, 2, 3, 7, and 10 after the intravitreal injection, and the amplitude of the a- and b-waves and the pSTR were measured. Surviving RGCs in the flat-mounted retinas were counted 10 days after axotomy. In addition to brimonidine, K252a (an inhibitor of tyrosine kinase phosphorylation of the Trk receptors), U0126 (a MAPK/ERK kinase inhibitor), and LY294002 (phosphoinositide 3-kinases [PI3Ks]) were also injected intravitreally into the left eye, and ERGs were recorded using the same protocol.



The pSTR amplitude increased significantly in the axotomized eyes with brimonidine, to 122.9 ± 5.0%, 161.8 ± 8.3%, and 133.6 ± 8.1% on days 1, 2, and 3 (P < 0.01), respectively, compared to the axotomized eyes treated with PBS (control). The increased pSTR amplitude returned to normal (103.6 ± 6.7%) on day 7, although there were a greater number of surviving RGCs in the treatment groups than in the controls. The intravitreal injection of K252a, U0126, or LY294002 significantly attenuated the increase in pSTR induced by intravitreal brimonidine (P < 0.01).



Intravitreal brimonidine enhanced the survival and electrophysiological activity of the RGCs in rats. The mechanism of this electrophysiological change may involve activation of the Trk-MAPK/ERK and Trk-PI3K signals.
a Department of Ophthalmology , Tohoku University Graduate School of Medicine , Sendai , Japan.
Masayoshi
M
Yukita
a Department of Ophthalmology , Tohoku University Graduate School of Medicine , Sendai , Japan.
Kazuko
K
Omodaka
b Department of Ophthalmology , Koshigaya Hospital, Dokkyo Medical University , Koshigaya , Japan.|c Department of Ophthalmology , Iwate Medical University School of Medicine , Morioka , Japan.
Shigeki
S
Machida
a Department of Ophthalmology , Tohoku University Graduate School of Medicine , Sendai , Japan.
Masayuki
M
Yasuda
a Department of Ophthalmology , Tohoku University Graduate School of Medicine , Sendai , Japan.
Kota
K
Sato
a Department of Ophthalmology , Tohoku University Graduate School of Medicine , Sendai , Japan.
Kazuichi
K
Maruyama
d Department of Advanced Ophthalmic Medicine , Tohoku University Graduate School of Medicine , Sendai , Japan.
Koji M
KM
Nishiguchi
a Department of Ophthalmology , Tohoku University Graduate School of Medicine , Sendai , Japan.|d Department of Advanced Ophthalmic Medicine , Tohoku University Graduate School of Medicine , Sendai , Japan.|e Department of Retinal Disease Control , Tohoku University Graduate School of Medicine , Sendai , Japan.
Toru
T
Nakazawa
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D000068438:Brimonidine Tartrate / Q000494:pharmacology*; D002470:Cell Survival; D003623:Dark Adaptation; D004596:Electroretinography / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D058449:Intravitreal Injections; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009900:Optic Nerve / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D015398:Signal Transduction
D058647:Adrenergic alpha-2 Receptor Agonists; D019208:Brain-Derived Neurotrophic Factor; D000068438:Brimonidine Tartrate; D004791:Enzyme Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020917:Receptor, trkA
Axonal injury; BDNF; brimonidine; retinal ganglion cell; scotopic threshold response