Cancers are very prevalent in our society today and there are still a limited number of treatments available. There are also limits to the treatments that are provided due to the negative side effects from the treatments. Chemotherapy is one of the main cancer treatments use today and the treatment is limited by a number of reasons with the main reason being the development of peripheral neuropathy.
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Peripheral neuropathy, pain caused due to damage of the peripheral nerves, during chemotherapy reduces the doses of chemotherapy that can be administered. This is especially noted after multiple course treatments with Paclitaxel. This is due to the activation of microglia and the activation and proliferation of astrocytes as well as cytokines which cause inflammation in the spinal dorsal horn to be released. This type of pain does not respond well to traditional analgesics.
Paclitaxel is administered for treatment of ovarian, lung and breast cancers but is limited due to it causing neuropathic pain as well as myelosuppression (reduction in bone marrow activity). While the myelosuppression can be mediated to a degree, there is currently no effective treatment of the neuropathy caused by Paclitaxel use. Cannabis preparations, opioids, amitriptyline and gabapentin have proved ineffective against the neuropathic pain experienced. Although cannabis and cannabinoids have been shown to be effective as an anti-emetic for those undergoing chemotherapy.
The endocannabinoid system is affected by two cannabinoid receptors CB1 and CB2. CB2 agonists have shown some promise in being neuroprotective and may offer treatment to prevent or relieve neuropathic pain. CB2 agonists are not psychotropic and so would not cause any unwanted effects such as those seen in CB1 agonists such as THC.
A CB2 agonist, MDA7 was synthesized and tested for absorption, metabolism, distribution, excretion and toxicity and did not show any significant toxicity issues. MDA7 was shown to improve allodynia induced by Paclitaxel as well as nerve litigation in rats. MDA7 did not impair loco-motor activities in the animals. This demonstrated potential for MDA7 could be used to prevent peripheral neuropathy.
MDA7 may be a possible preventative as opposed to a treatment for neuropathic pain. MDA7 prevents mechanical allodynia in mice and rats without compromising the anti-neoplastic effect of Paclitaxel. CB2 antagonists were able to effectively prevent the effect of MDA7 which suggests that MDA7’s therapeutic action directly involves the CB2 receptors being activated.
MDA7 interfered with the neuroinflammatory response causes by Paclitaxel as well as reduced microglia and astrocytes. This was also seen in reduced secretion of inflammation causing mediators in in vitro and in vivo models. The use of MDA7 in further research may also assist in the understanding of the mechanisms whereby CB2 agonists regulate the negative feedback loop of neuroinflammatory processes. This may lead to CB2 targeted strategies for developing neuroprotection in the future.
These findings suggest that there may be a possible therapeutic approach to prevent peripheral neuropathy in cancer patients undergoing chemotherapy. This may allow for higher doses of the chemotherapy agent and more aggressive treatment of the cancer without the risk of severe neuropathic pain.