Vincristine is the
drug of choice for
Hodgkin's lymphoma,
acute lymphoblastic leukemia, and
non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive
dose reduction. The available drugs used for
vincristine-induced
neuropathic pain (VINP) have a range of safety, efficacy, and tolerability issues prompting a search for new
therapies.
5,7-Dimethoxycoumarin (5,7-DMC) also known as
citropten, is a natural
coumarin found in the
essential oils of citrus plants such as
lime, lemons, and bergamots, and it possesses both
antidepressant and anti-inflammatory effects. This study was designed to investigate the possible
analgesic and antiallodynic effects of 5,7-DMC in a murine model of VINP.
Vincristine was administered to groups of BALB/c male mice (0.1 mg/kg intraperitoneally) once daily for 14 days to induce VINP.
Thermal hyperalgesia and
mechanical allodynia were quantified using the tail immersion test and von Frey filament application method. The levels of monoamine
neurotransmitters and
vitamin C in frontal cortical, striatal and hippocampal tissues, as well as the TNF-α level in plasma, were quantified using high performance liquid chromatography and ELISA respectively. On day 15 of the protocol, acute treatment with 5,7-DMC clearly reversed VINP
thermal hyperalgesia, mechanical static
allodynia, mechanical dynamic
allodynia, and cold
allodynia. The activity of 5,7-DMC against
hyperalgesia and
allodynia was inhibited by pretreatment with
ondansetron but not
naloxone, implicating a
5-HT3 receptor involvement. VINP
vitamin C levels were restored by 5,7-DMC in the frontal cortex, and changes in
serotonin,
dopamine,
adenosine,
inosine and
hypoxanthine levels caused by
vincristine were reversed either fully or partially. Additionally, the
vincristine-induced rise in hippocampal
serotonin,
dopamine,
inosine and striatal
serotonin was appreciably reversed by 5,7-DMC. 5,7-DMC also reversed the
vincristine-induced increase in the plasma level of TNF-α. In negating the changes in the levels of some
neurotransmitters in the brain caused by
vincristine, 5,7-DMC showed stronger effects than
gabapentin. It was concluded that, there is a potential role of 5-HT3 receptors and monoamines in the amelioration of VINP induced by 5,7-DMC, and the use of this compound warrants further investigation.