Balipodect

Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform phosphodiesterase 10A (PDE10A) might be a target for analgesic therapy.

In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors.

PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD, 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (two-way ANOVA, group, F[1,18] = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund’s adjuvant (F[1,14] = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920.

Collectively, the data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.