Research group: Alessia Pascale

Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development.
VEGF-A (vascular endothelial growth factor A) has a detrimental role in DR development and progression, being a well-known vasopermeability factor and a mediator of neovascularization. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of VEGF, via the mRNA-binding Hu-antigen R (HuR) protein. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, we also set up proper in vitro models that can allow to better identify promising effective molecules.
Besides VEGF, P2X7 receptor (P2X7R), an ionotropic ligand gated receptor, is emerging as an intriguing pharmacological target in the retina for the modulation of neuroinflammation, which exacerbates the disease course. The possibility exists that, through Ca2+ influx, P2X7 induces the stimulation of PKC that activates HuR, thus promoting, down-stream, an increased expression of VEGF. Therefore, we aim to explore the potential existence of this new cascade and to identify, through a drug repurposing approach, new molecules able to modulate P2X7 receptor. Notably, already approved drugs would be used for a different therapeutic indication, avoiding the cost of expensive studies that are usually necessary to develop new chemical entities.

Selected Publications:

• “The PKCβ/HUR/VEGF pathway in diabetic retinopathy”. Amadio M., Bucolo C., Leggio G.M., Drago F., Govoni S. and Pascale A. Biochem. Pharmacol. 80: 1230-1237, 2010.
• “Nanosystems based on siRNA silencing HUR expression counteract diabetic retinopathy in rat”. Amadio M., Pascale A.*, Cupri S., Pignatello R., Osera C., D’Agata V., D’Amico A.G., Leggio G.M., Ruozi B., Govoni S., Drago F., Bucolo C. Pharmacol Res.111:713-20, 2016. *co-authorship.
• Effect of troxerutin in counteracting hyperglycemia-induced VEGF upregulation in endothelial cells. A new option to target early stages of diabetic retinopathy?” Fahmideh F., Marchesi N., Campagnoli L.I.M., Landini L., Barbieri A., Govoni S., Pascale A. Frontiers in Pharmacology, Section “Experimental Pharmacology and Drug Discovery” 13: 951833, 2022.
• “RNA binding proteins in senescence: a potential common linker for age-related diseases?” Varesi A., Campagnoli L.I.M., Barbieri A., Rossi L., Ricevuti G., Esposito C., Marchesi N., Pascale A. Ageing Research Reviews 88:101958, 2023.

Links:
https://scienzedelfarmaco.dip.unipv.it/it/ricerca/aree-di-ricerca/farmacologia/neurofarmacologia-cellulare-e-molecolare
https://www.researchgate.net/profile/Alessia_Pascale