Protein tyrosine phosphatase 1B contributes to neuropathic pain by aggravating NF-κB and glial cells activation-mediated neuroinflammation via promoting endoplasmic reticulum stress.

BACKGROUND: Neuropathic pain is a prevalent and highly debilitating condition that impacts millions of individuals globally. Neuroinflammation is considered a key factor in the development of neuropathic pain. Accumulating evidence suggests that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in regulating neuroinflammation. Nevertheless, the specific involvement of PTP1B in neuropathic pain remains largely unknown. This study aims to examine the impact of PTP1B on neuropathic pain and unravel the underlying molecular mechanisms implicated. METHODS: In the current study, we evaluated the paw withdrawal threshold (PWT) of male rats following spared nerve injury (SNI) to assess the presence of neuropathic pain. To elucidate the underlying mechanisms, western blotting, immunofluorescence, and electron microscopy techniques were employed. RESULTS: Our results showed that SNI significantly elevated PTP1B levels, which was accompanied by an increase in the expression of endoplasmic reticulum (ER) stress markers (BIP, p-PERK, p-IRE1α, and ATF6) and phosphorylated NF-κB in the spinal dorsal horn. SNI-induced mechanical allodynia was impaired by the treatment of intrathecal injection of PTP1B siRNA or PTP1B-IN-1, a specific inhibitor of PTP1B. Moreover, the intrathecal administration of PTP1B-IN-1 effectively suppressed the expression of ER stress markers (BIP, p-PERK/p-eIF2α, p-IRE1α, and ATF6), leading to the inhibition of NF-κB, microglia, and astrocytes activation, as well as a decrease in pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1ß. However, these effects were reversed by intrathecal administration of tunicamycin (Tm, an inducer of ER stress). Additionally, intrathecal administration of Tm in healthy rats resulted in the development of mechanical allodynia and the activation of NF-κB-mediated neuroinflammatory signaling. CONCLUSIONS: The upregulation of PTP1B induced by SNI facilitates the activation of NF-κB and glial cells via ER stress in the spinal dorsal horn. This, in turn, leads to an increase in the production of pro-inflammatory cytokines, thereby contributing to the development and maintenance of neuropathic pain. Therefore, targeting PTP1B could be a promising therapeutic strategy for the treatment of neuropathic pain.

Hederagenin Upregulates PTPN1 Expression in Aß-Stimulated Neuronal Cells, Exerting Anti-Oxidative Stress and Anti-Apoptotic Activities.

Alzheimer's disease (AD) is a prevalently neurodegenerative disease characterized by neuronal damage which is associated with amyloid-ß (Aß) accumulation. Hederagenin is a triterpenoid saponin, exerting anti-apoptotic, anti-oxidative, anti-inflammatory, anti-tumoral, and neuroprotective activities. However, its role in AD progression is still obscure. The aim of this study was to explore the influences of hederagenin on Aß-caused neuronal injury in vitro. Neuronal cells were treated with Aß25-35 (Aß) to establish a cellular model of AD. Cell viability was assessed using cell counting kit-8 (CCK-8). Oxidative stress was evaluated by detecting reactive oxygen species (ROS) generation and superoxide dismutase (SOD) activity. Apoptosis was investigated using TUNEL staining and caspase-3 activity assays. Protein tyrosine phosphatase nonreceptor type 1 (PTPN1) was screened by bioinformatics analysis. Protein levels of PTPN1 and protein kinase B (Akt) were measured by western blotting. Hederagenin (2.5, 5, and 10 µM) alone did not affect viability of neuronal cells, but relieved Aß-induced viability reduction. Hederagenin mitigated Aß-induced increase in ROS accumulation and decrease in SOD activity. Hederagenin attenuated Aß-induced increase in apoptotic rate and caspase-3 activity. PTPN1 was screened as a target of hederagenin against AD by bioinformatics analysis. Hederagenin treatment resisted Aß-induced decrease in PTPN1 mRNA and protein levels in neuronal cells. PTPN1 silencing attenuated the suppressive functions of hederagenin in Aß-stimulated oxidative stress and apoptosis. Hederagenin mitigated Aß-induced Akt signaling inactivation by upregulating PTPN1 expression. In conclusion, hederagenin attenuates oxidative stress and apoptosis in neuronal cells stimulated with Aß by promoting PTPN1/Akt signaling activation.

Cladosporamide A, a new protein tyrosine phosphatase 1B inhibitor, produced by an Indonesian marine sponge-derived Cladosporium sp.

Cladosporamide A (1), a new protein tyrosine phosphatase (PTP) 1B inhibitor, was isolated together with a known prenylated flavanone derivative (2) from the culture broth of an Indonesian marine sponge-derived Cladosporium sp. TPU1507 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was elucidated based on 1D and 2D NMR data. Compound 1 modestly inhibited PTP1B and T-cell PTP (TCPTP) activities with IC50 values of 48 and 54 µM, respectively. The inhibitory activity of 2 against PTP1B (IC50 = 11 µM) was approximately 2-fold stronger than that against TCPTP (IC50 = 27 µM).