Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

Abstract

Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160 ROCK /Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75 NTR ) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway.

β-Arrestin 1 Inhibits the GTPase-Activating Protein Function of ARHGAP21, Promoting Activation of RhoA following Angiotensin II Type 1A Receptor Stimulation

“…Inhibitor compounds have been described for Rho kinase (ROCK) (8), an important downstream effector of RhoA, and peptide-derived ligands that target the p75 neurotrophin receptor upstream of RhoA have also been developed to modulate RhoA/ROCK activity (20). To date, however, there has been a lack of compounds directed at either RhoGEFs or RhoGAPs (28).…”

A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury

“…The compound was subsequently reported to inhibit Ab-induced cell death in hippocampal, cortical, and septal neurons, decrease activity in a range of toxic/apoptotic signaling pathways, and reverse Ab-mediated neuritic dystrophy and impairment of hippocampal long-term potentiation [33]. Furthermore, LM11A-31 has been shown to inhibit chemotherapeutic agentinduced rhoA signaling [34], and has shown excellent oral absorption, blood-brain barrier penetration and tolerability, and mitigates pathology in models of spinal cord injury and Alzheimer's disease [35,36]. In spinal cord injury, the compound promoted survival of oligodendrocytes, preserved myelin, and improved motor function, and was shown to reduce the interaction of proNGF and p75 NTR in vivo [35].…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…Platinum agents (cisplatin, oxaliplatin, carboplatin) induce neuronal apoptosis in the DRG through the formation of DNA-platinum complexes and early p38 and ERK1/2 activation. 29,30 Recently, James et al 31 also reported that cisplatin induced neurite degeneration of primary rat neurons in line with the observed axonal neuropathy in patients. Notably, the neurotoxicity of cisplatin can be alleviated by inhibiting the Rho signaling pathway.…”