Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Abstract

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient’s quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca2+ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30–100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice

“…However, most of these therapies exhibited moderate efficacy and significant side effects such as somnolence, constipation, tolerance, and dizziness [ 60 ]. In addition, some treatments only improved neuropathy or one of the emotional disorders associated with chemotherapy-induced neuropathic pain [ 61 , 62 , 63 ], but only a few studies evaluated the possible effects of different treatments in the management of PIPN-associated mood disorders [ 13 , 64 , 65 ]. In this line, this study demonstrated that treatment with HRW inhibited neuropathy and avoided the cognitive and emotional deficits associated.…”

Resveratrol inhibits Cell Cycle Dynamics, Caspase Activation, and Programmed Cell Death: Implications for Cancer Treatment in MCF-7 Cells"

“…This is a result of increased production of free oxygen radicals aftertreatment and the release of damaged mitochondrial debris [45]. Resveratrol prevents cell survival, promotes programmed cell death in MCF-7 cells [46], and enhances the anti-cancer effects of paclitaxel in human liver cancer cells HepG22. Resveratrol induces intrinsic cell death dependent on caspases associated with increased oxidative stress mediated by oxygen and nitrogen in its cells [47].…”

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

“…Indeed, connections have been observed between the activity of CAs and pain reducing HCO 3 - -dependent depolarization via GABA A receptors when the function of the neuron-specific potassium-chloride (KCl) cotransporter KCC2 is compromised [ 54 , 55 ]. The type of moiety bearing the phenol portion of the tail seems to be a crucial factor that impacts activity against different isoforms, as demonstrated in the case of hCA IX, where a phenyl moiety showed a 10-fold increase in potency compared to other reported derivatives [ 53 ].…”