Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation

Abstract

Aims. Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis. Methods. CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A γ-secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-α, and IL-1β in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining. Results. Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF-α and IL-1β. Conclusion. Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.

Bone marrow mesenchymal stem cell-derived exosomes shuttling miR-150-5p alleviates mechanical allodynia in rats by targeting NOTCH2 in microglia

“…The presence of NOTCH1 irritated mechanical allodynia and thermal hyperalgesia threshold and induced TNF-α level in dorsal root ganglions from neuropathic rats (Chen et al 2017 ). NOTCH intracellular domain (NICD) was upregulated in SDH after cystitis, and NOTCH inhibitor treatment attenuated mechanical allodynia and microglial activation (Chen et al 2021 ).…”

Broaden Horizons: The Advancement of Interstitial Cystitis/Bladder Pain Syndrome

“…Recent studies demonstrated that TRPA1, TRPV1, and TRPM3 were involved in the development of chronic pain in IC/BPS, and the inhibition of these channels was proven effective in alleviating the severity of pain [ 165 , 170 ]. Similarly, from the results of the von Frey filament experiment in Chen’s study [ 171 , 172 ], neuregulin-1-ErbB and Notch1 signaling might boost the activation of microglia in cyclophosphamide-induced cystitis and, therefore, could be two potential targets for the treatment of allodynia.…”

Involvement of NOTCH1-mediated Microglia Activation in Neuromodulation of Chronic Prostatitis-related Pain

“…Minimally invasive treatments (including spinal cord and peripheral nerve stimulation) may become promising for the treatment of refractory CP-related pain (3). Spinal microglia are important immune cells in the central nervous system (CNS), and they can cause pain by secreting inflammatory mediators in response to the activation of NOTCH signaling pathways (4). Our previous pilot study also reveals that NOTCH1 is involved in the transmission of signals in the glial cells, which mediates neuropathic pain and NOTCH1 is one of the key molecules regulating pain (unpublished data).…”