Similarly, systemic overexpression of the human Epo transgene resulted in the 2 fold enhanced level of EPO protein in the retina, and led to photoreceptor safety against light induced harm . Its relevant to note that in many instances, safety of photoreceptors by EPO remedy was not as complete as after HP, therefore suggesting that hypoxia triggers additional protective mechanisms. Whereas it seems clear that EPO can safeguard photoreceptor cells against phototoxic strain, safety towards inherited photoreceptor degeneration would seem to depend on the model and hence to the unique molecular pathway which leads to cell death. Transgenic Epo overexpression or repetitive intraperitoneal injections of rhEPO in rd1 and VPP mice didn’t rescue photoreceptor cells . Similarly, Rex and co employees demonstrated that photoreceptors within the rd1 mouse have been not protected by the expression of an Epo transgene in skeletal muscular tissues following AAV mediated transfer . On the other hand, the identical approach appreciably prevented degeneration during the rds mouse , as did the subretinal injection of rhEPO .
Surprisingly, safety during the rds mouse was only achieved after intramuscular but not immediately after intraocular injection of AAV Epo vectors. The observation that EPO isoforms produced while in the retina soon after AAV mediated gene transfer differed depending on the retinal cell kind transduced, as well as differed peptide synthesis selleck chemicals from the two physiological EPO and EPO created by a transgene in skeletal muscle cells might possibly aid to make clear this locating. Also, giant area EPO concentrations achieved as a result of intraocular expression of a transgene may not be optimal to mediate the neuroprotective impact . Alternatively, certain posttranslational modifications apart from glycosylation might possibly also be important for protection. The mechanisms top to photoreceptor protection just after intramuscular Epo gene transfer are even now unclear. Even so, considering that expression of non erythropoietic forms of EPO resulted only in a slight raise with the hematocrit but nonetheless protected neuronal cells efficiently , increased tissue oxygenation through a rise in the erythrocyte population might not be the basis for that protection.
The failure of EPO to guard photoreceptors SMI-4a selleck during the rd1, rd1 and VPP versions also suggests that EPO may not be universally neuroprotective, but rather might possibly interfere only with specific apoptotic mechanisms. These mechanisms appear to be activated inside the rds mouse but not in other versions of retinal degeneration investigated to date. Hence, to define the mechanisms of protection by EPO, it’ll be crucial to elucidate the various apoptotic pathways because they happen inside the different models of retinal degeneration . Pleiotropic results from the diabetic retina Elevated ranges of EPO protein are already detected from the vitreous of eyes with diabetic macular edema and in post mortem eyes of diabetic sufferers .