Mechanisms of Astrocyte Contribution to Bortezomib-Induced Peripheral Neuropathy

Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma and other non-solid malignancies, alone or in combination with other chemotherapy drugs. Like other chemotherapeutic agents, bortezomib treatment is frequently accompanied by chemotherapy-induced peripheral neuropathy (CIPN) that may be dose-limiting, adversely affecting quality of life and prognosis. The mechanisms behind bortezomib-induced peripheral neuropathy (BIPN) and CIPN overall are largely unknown. Recent findings in other pain models have indicated substantial involvement of glial cells in chronic pain. Although injury models have shown activation of both astrocytes and microglia following insult, research in other CIPN models has shown astrocytic activation in the absence of microglial activation. The central hypothesis of this dissertation is that the activity of astrocytes is correlated with behavioral changes observed in a rat model of BIPN in a manner that may directly contribute to these changes in behavior. To investigate this, the work of this dissertation 1) established the multimodal changes to behavior and showed increases in spinal neuron firing in BIPN, 2) quantified activity of astrocytes and whether changes were prevented by minocycline, an anti-inflammatory drug that vi prevents glial activation, and 3) quantified changes in connexin 43, GLT-1, and GLAST to assess whether astrocytic glutamate transport may be altered in BIPN. The results observed in the first aim were that the rat BIPN model is characterized by selective mechanical hypersensitivity and a significant increase in wide dynamic range (WDR) neuron firing rates and after-discharges. In the second aim, astrocytes in the BIPN model were activated in a manner that paralleled the behavioral changes. Animals co-treated with minocycline resembled saline-treated animals in both astrocytic activation and behaviors. The results in the third aim were that astrocytic gap junctions were increased and GLAST expression was decreased at the height of mechanical sensitivity. Minocycline-treated animals resembled saline-treated animals in expression of these proteins, as well. The overall conclusion was that astrocyte activity closely paralleled behaviors in the BIPN model in a manner that may be explained by their role in glutamate trafficking