Abstract
Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity.
Highlights
Liu Jun Zi Tang (LJZT), a famous Chinese herbal formula and Kampo medicine, known as Rikkunshito in Japan, has been used for several hundred years
Because treatment with 10 μM of cisplatin resulted in approximately 50% cell death and 100 μg/mL of LJZT exerted the highest protective effect, these two dosages were adopted in this study
We revealed that except for mitochondrial free radical formation (Figure 4A) and pro-apoptotic factor release (Figure 6), cisplatin resulted in decreased mitochondrial membrane potential (Figure 4B) and mitochondrial fragmentation (Figure 7A), which was consistent with previous findings [50], and elicited mitochondrial dysfunction
Summary
Liu Jun Zi Tang (LJZT), a famous Chinese herbal formula and Kampo medicine, known as Rikkunshito in Japan, has been used for several hundred years. Chemotherapy-induced peripheral neuropathy is the most common neurological complication associated with cancer treatment, with vincristine, paclitaxel, oxaliplatin, and cisplatin being the most neurotoxic compounds [9]. This neurotoxicity may lead to disability and decreased quality of life. The painful sensations may involve shooting or electric shock-like pain, non-evoked burning, as well as mechanical or thermal allodynia or hyperalgesia [10] Among these medications, cisplatin has played a major role in cancer chemotherapy for many years and is a commonly-used antineoplastic drug in clinical treatment [11]. LJZT is known to alleviate chemotherapy-induced gastrointestinal side effects, its neurological and pain-relieving functions have rarely been investigated. In this study, potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity were explored
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