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Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system.

ABSTRACT: Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models.To explore the potential of CB(2) agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB(2)-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB(2)(+/+) and CB(2)(-/-) mice. We hypothesized that the CB(2) receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways.We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB(2)(-/-) mice and was blocked by CB(2) antagonists, suggesting that MDA7's action directly involves CB(2) receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB(2) expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models.Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.

SUBMITTER: Naguib M

PROVIDER: S-EPMC3334436 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system.

Naguib Mohamed M Xu Jijun J JJ Diaz Philippe P Brown David L DL Cogdell David D Bie Bihua B Hu Jianhua J Craig Suzanne S Hittelman Walter N WN

Anesthesia and analgesia 20120305 5

<h4>Background</h4>Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models.<h4>Methods< ...[more]

PMID: 22392969

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Project description:Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as ?(9)-tetrahydrocannabinol (?(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown.We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid ?(9)-THC. We also explored the site and possible mechanism of action of AM1710.Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and ?(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to ?(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-? and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice.Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.

Project description:Neuroinflammation plays a major role in postoperative cognitive dysfunction (POCD). Accumulated evidence indicates that cannabinoid receptor type 2 (CB2R) can mediate anti-inflammatory and immunomodulatory effects in part by controlling microglial activity. However, the impact of CB2R on postoperative cognition has not been investigated. We hypothesized that CB2R is involved in surgery-induced cognitive impairment in adult mice.Adult C57BL/6 mice were subjected to intramedullary fixation surgery for tibial fracture under isoflurane anesthesia and CB2R agonist (JWH133) or CB2R antagonist (AM630) treatment. The mice were trained 24 h prior to surgery using a fear conditioning protocol and assessed in a novel context on postoperative days 1, 3, and 7 to evaluate cognitive function. Open-field testing was performed to evaluate the locomotor activity of the mice. The expression levels of IL-1β, TNF-α, MCP-1, and CB2R in the hippocampus and prefrontal cortex were assessed by Western blotting; the expression of microglial marker CD11b in the CA1 area of the hippocampus and medial prefrontal cortex was assessed by immunostaining.The mice displayed no changes in locomotor activity after surgery and drug treatments. The mice exhibited impaired hippocampal-dependent memory accompanied by an increased expression of proinflammatory factors in the hippocampus and prefrontal cortex 1, 3, and 7 days after surgery, while hippocampal-independent memory remained unaffected at the same time points. JWH133 treatment attenuated surgery-induced memory loss, while AM630 treatment aggravated surgery-induced memory loss, paralleled by a decreased or increased expression of proinflammatory factors in the hippocampus and prefrontal cortex. The expression of CB2R in the hippocampus and prefrontal cortex was upregulated following surgery; however, it was downregulated by postoperative treatment with JWH133. Similarly, the expression of CD11b in the CA1 area of the hippocampus and medial prefrontal cortex was upregulated following surgery and downregulated by postoperative treatment with JWH133.These findings indicate that CB2R may modulate the neuroinflammatory and cognitive impairment in a mouse model of orthopedic surgery, and the activation of CB2R may effectively ameliorate the hippocampal-dependent memory loss of mice in the early postoperative stage.

Dataset Information

Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system.

Publications

Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system.

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