Protective effects of distinct proline-rich oligopeptides from B. jararaca snake venom against oxidative stress-induced neurotoxicity

Abstract

The low molecular mass fraction from Bothrops jararaca snake venom contains proline-rich peptides (Bj-PROs), also known as bradykinin-potentiating peptides (BPPs), which were described as neuroprotective against H₂O₂-induced oxidative stress. Recently, we reported that the neuroprotective action of Bj-PRO-10c (<ENWPHPQIPP) is a result of an increase in the expression and activity of argininosuccinate synthase (AsS), thereby improving increase L-arginine synthesis. It is proposed that formation agmatine and polyamines from L-arginine metabolism are neuroprotective, reducing lipid peroxidation, oxidative stress, and maintenance of the mitochondrial membrane. In the present study, Bj-PRO-5a (<EKWAP), Bj-PRO-7a (<EDGPIPP), Bj-PRO-11e (<EARPPHPPIPP), and Bj-PRO-AP (<EARPPHPPIPPAP) - with different structure-activities, in particular on AsS expression and activity - were selected to study their protective properties on H₂O₂-induced oxidative stress in SH-SY5Y cells. Bj-PROs tested were neuroprotective, but Bj-PRO-5a and Bj-PRO-7a increased cell viability by more than 85% in the presence of H₂O₂ (450 μM) and reduced the oxidative stress markers. AsS, iNOS, and NF-ĸB expressions were not involved in the neuroprotective mechanism for both peptides, in contrast to Bj-PRO-10c, as reported in the literature. Bj-PRO-5a is a neuroprotector peptide that decreases ROS production, NO levels lipid peroxidation, and changes in mitochondrial membrane permeability caused by H₂O₂ exposition. The neuroprotective property of Bj-PRO-7a against H₂O₂ is also related to decreased ROS production and lipid peroxidation but without altering NO levels. These results show that the protective effects of different Bj-PROs against oxidative stress can be explained by distinct mechanisms independent of an increase in L-arginine bioavailability arising from AsS activity. Further studies are now needed to reveal the details of the neuroprotective mechanisms exerted by Bj-PROs.

Keywords: Argininosuccinate synthase; Bothrops jararaca; Bradykinin-potentiating peptides; Neuroprotective; Oxidative stress; Proline-rich peptides.