Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension.
Open angle glaucoma is defined as a progressive and time-dependent death of retinal ganglion cells concomitant with high intraocular pressure, leading to loss of visual field. Because neurotrophins are a family of growth factors that support neuronal survival, we hypothesized that quantitative and qualitative changes in neurotrophins or their receptors may take place early in ocular hypertension, preceding extensive cell death and clinical features of glaucoma. We present molecular, biochemical, and phenotypic evidence that significant neurotrophic changes occur in retina, which correlate temporally with retinal ganglion cell death. After 7 days of ocular hypertension there is a transient up-regulation of retinal NGF, while its receptor TrkA is up-regulated in a sustained fashion in retinal neurons. After 28 days of ocular hypertension there is sustained up-regulation of retinal BDNF, but its receptor TrkB remains unchanged. Throughout, NT-3 levels remain unchanged but there is an early and sustained increase of its receptor TrkC in Müller cells but not in retinal ganglion cells. These newly synthesized glial TrkC receptors are truncated, kinase-dead isoforms. Expression of retinal p75 also increases late at day 28. Asymmetric up-regulation of neurotrophins and neurotrophin receptors may preclude efficient neurotrophic rescue of RGCs from apoptosis. A possible rationale for therapeutic intervention with Trk receptor agonists and p75 receptor antagonists is proposed.
Rudzinski
Marcelo
M
Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
Wong
Tak-Pan
TP
Saragovi
H Uri
HU
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005902:Glaucoma, Open-Angle / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D009798:Ocular Hypertension / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC