In a rotenone rat model of Parkinson's disease, the hemoglobin-derived peptide LVV-H3 reduced calcineurin activity in brain, spinal cord, lymphoid organs and plasma and partially normalized altered IL-2 and TNFα levels, effects that overlapped but were not identical to the calcineurin inhibitor…

By demonstrating that an endogenous peptide can modulate calcineurin signaling and peripheral/CNS cytokine profiles in a mitochondrial toxin PD model, this study identifies a biologically plausible, targetable mechanism (CaN-driven inflammation) with translational potential for early-stage PD…

Dysregulation of intracellular Ca2+ levels and activation of the Ca2+/calmodulin-dependent phosphatase calcineurin (CaN) contribute to neurodegeneration and inflammatory responses associated with the Parkinson's disease (PD) pathogenesis. Hence, regulation of CaN activity may be beneficial in PD. Hemorphins, endogenous hemoglobin-derived peptides, play modulatory role in the brain and immune system in experimental pathologies. The effect of hemorphin LVV-H3 on CaN activity and proinflammatory cytokines (IL-2, TNFα) in the CNS (brain, spinal cord), peripheral tissues (thymus, spleen) and plasma was studied using a rotenone-induced PD model in rats. Rotenone was administered at 0.5 mg/kg (s.c.) for 40 days. Hemorphin LVV-H3 (1 mg/kg; i.p.) was administered in pretreatment and posttreatment regimens. To assess LVV-H3 effects on cytokines levels associated with CaN signaling, rats received the CaN inhibitor cyclosporine A (CsA; 5 mg/kg; i.p.) alone or combined with LVV-H3 in rotenone-injected rats. Chronic rotenone administration significantly increased CaN activity in the brain and spinal cord (by 76%), thymus (by 255%), spleen (by 45%), and plasma (by 59%) compared to controls. LVV-H3 posttreatment reduced CaN activity in these tissues. IL-2 and TNFα levels were altered differently by rotenone; for example, IL-2 increased and TNFα decreased in the brain. LVV-H3 pretreatment reversed these changes, decreasing IL-2 and increasing TNFα compared to rotenone-injected rats. Results indicate that LVV-H3-mediated cytokine regulation is partially, but not entirely mediated through CaN-dependent mechanisms. Modulation of CaN activity and cytokine levels suggests hemorphin as a potential regulatory agent against rotenone-induced changes in the CNS and peripheral tissues.