Lithium Attenuates Peripheral Neuropathy Induced by Paclitaxel in Rats

Abstract

As a cancer chemotherapeutic agent, paclitaxel (Taxol Ò ) causes dose-related peripheral neuropathy in human beings. The mechanisms underlying this toxicity are currently unknown, and there are no validated treatments for its prevention or control. To assess whether lithium as a pre-treatment and at subtherapeutic dose could prevent the peripheral neuropathy produced by it, rats were treated with paclitaxel (2 mg ⁄ kg i.p. every other day for a total of 16 times) and ⁄ or lithium chloride (300 mg ⁄ l) via water supply. General toxicity and body-weight were measured regularly during the experiment. To evaluate the sensory and motor neuropathy hot-plate, open-field test and nerve conduction velocity were used. In rats treated with only paclitaxel, there was behavioural, electrophysiological and histological evidence of a mixed sensorimotor neuropathy after 16 injections. Lithium robustly reduced the rate of mortality and general toxicity. Paclitaxel-induced sensorimotor neuropathy was significantly improved as indicated by changes in hotplate latency, total distance moved and a significant increase in sciatic, sural and tail sensory or motor nerve conduction velocity. The same results were observed in histopathological examinations; however, dorsal root ganglion neurons did not significantly change in the paclitaxel-treated groups. These results suggest that lithium, at subtherapeutic doses, can prevent both motor and sensory components of paclitaxel neuropathy in rats. Thus, lithium at these doses, as an inexpensive and relatively safe salt, may be useful clinically in preventing the neuropathy induced by paclitaxel treatment.Paclitaxel is an effective anti-tumour agent initially isolated from the bark of the pacific yew tree, Taxus brevifolia, and is regularly used to treat long, ovarian cancer either by itself or in combination with other anti-tumour agents [1][2][3]. Paclitaxel causes excessive tubulin polymerization leading to mitotic arrest and thus inducing apoptosis in dividing cells [4].Microtubules play an important role in cellular functions such as membrane and cellular scaffolding, intracellular transport of organelles or proteins and transmission of signals initiated at cell surface receptors. Thus, microtubules interfering agents like vincristine or paclitaxel may disturb non-neoplastic cells such as nerves and finally cause apoptosis. Hence, peripheral neuropathy is one of the most frequent side effects of these two drugs that usually result in dose modification and changes in the treatment plan [5][6][7][8].As a mood stabilizer, lithium is commonly prescribed for bipolar disorders, and although its mechanism of action remains unknown, it is well established that lithium exerts some of its therapeutic effects through G-protein-coupled pathway, glycogen synthase kinase-3 (GSK3b), inositol monophopsphate and nitric oxide-dependent pathways and augmentation of serotonin function in the central nervous system [9,10]. Previous studies have reported that lithium has neuroprotective effects. The...

Inhibition of Paclitaxel-induced Decreases in Calcium Signaling

“…In the past, lithium and ibudilast were tested as potential treatment options for the treatment of Taxol-induced peripheral neuropathy; however, neither compound was previously considered as a preventative measure against peripheral neuropathy (22,23,27,28). This study clearly shows that these candidate compounds are able to inhibit chemotherapy-induced changes in neuronal cells.…”

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

“…Moreover, it has an excellent antitumor activity in phase III breast cancer during clinical trials [4] . Paclitaxel is a microtubule stabilizing agent active against cancer cells and also the neurons are affected by paclitaxel [5] .…”

“…The incidence of paclitaxel-induced peripheral neuropathy is high ranging from 57%-83% accompanied with severity in 2%-33% of patients [2][3][4][5][6][7] . In vivo toxicity of paclitaxel was reported in mature neurons in the hippocampus [8] .…”

“…The pathogenesis of CIPN is attributed to the development of axonopathy and myelinopathy [4][5][6][7][8][9][10] . Paclitaxel was found to be concentrated in dorsal root ganglia then in sciatic nerve and spinal cord due to paclitaxel transport along centrifugal and centripetal branches of the dorsal root ganglia neuron axon [12] .…”

“…Several neuroprotective agents have been introduced to ameliorate the neurotoxicity associated with paclitaxel as acetyl-L-carnitine [13] , amifostine, nerve growth factor [12] , glutamine [2][3][4][5][6] , vitamin E [14] , lithium [5] , and benfotiamine [1] but they have limited successful protective effect.…”