Neurokinin-1 Receptor Antagonists Protect Mice from CD95- and Tumor Necrosis Factor-α-Mediated Apoptotic Liver Damage

Abstract

Previously, we have shown that primary afferent neurons are necessary for disease activity in immune-mediated liver injury in mice. These nerve fibers are detectable by substance P (SP) immunocytochemistry in the portal tract of rodent liver. Antagonists of the neurokinin-1 receptor (NK-1R), which is the prime receptor of SP, prevented liver damage by suppressing the synthesis of proinflammatory cytokines. Here, we investigated the influence of primary afferent nerve fibers, SP, and NK-1 receptor antagonists on hepatocyte apoptosis in vivo induced by administration of activating anti-CD95 monoclonal antibody (mAb) to mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment prevented CD95-mediated activation of caspase-3, measured as enzymatic activity in liver homogenates or by demonstration of hepatocellular immunoreactivity for active caspase-3 in liver slices, and liver damage. This effect was reversed by administration of SP to anti-CD95 mAb-treated mice In conclusion, SP, probably by binding to its receptor on hepatocytes, might aggravate apoptotic signals in these cells. Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent liver cell apoptosis in vivo, they might be suitable drugs for treatment of immunemediated liver disease.

A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage

“…. ) [77]. Moreover, the specific binding of L-733,060 to the NK1 receptor has been demonstrated in human breast carcinoma [70].…”

Involvement of substance P and the NK-1 receptor in human pathology

“…NK-1 receptor antagonists prevent hepatocyte apoptosis, meaning that by binding to NK-1 receptors in hepatocytes SP might aggravate apoptotic signals in these cells (Bang et al 2003). Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent hepatocyte apoptosis, they might be considered potent drugs for the treatment of inflammatory liver disease, most likely through an inhibition of the effects of SP (Bang et al 2003(Bang et al , 2004.…”

Disease-Related Changes in TRPV1 Expression and Its Implications for Drug Development

“…Furthermore, protection of autoimmune diabetes by capsaicin could be due to change in antigen concentration at the site of inflammation (97). TRPV1 is shown to have beneficial effect on several immune diseases such as neurological symptoms associated with autoimmune encephalomyelitis, increased immune response genes in chronic fatigue syndrome and fibromyalgia syndrome and loss of hepatocytes in immune mediated liver injury [318][319][320] and dermatitis [321]. TRPV1 has been shown to be involved in the progression of allergic contact dermatitis (ACD).…”