The cancer chemotherapeutic agent paclitaxel (Taxol) reduces hippocampal neurogenesis via down-regulation of vesicular zinc

Abstract

Chemotherapy-induced cognitive impairment (CICI) is increasingly recognized as a major unwanted side effect of an otherwise highly valuable life-saving technology. In part, this awareness is a result of increased cancer survival rates following chemotherapy. Altered hippocampal neurogenesis may play a role in mediating CICI. In particular, zinc could act as a key regulator of this process. To test this hypothesis, we administered paclitaxel (Px) to male C57BL/6 mice for set time periods and then evaluated the effects of Px treatment on hippocampal neurogenesis and vesicular zinc. We found that vesicular zinc levels and expression of zinc transporter 3 (ZnT3) were reduced in Px-treated mice, compared to vehicle-treated mice. Moreover, Px-treated mice demonstrated a significant decrease in the number of neuroblasts present. However, no difference in the number of progenitor cells were observed. In addition, zinc supplementation by treatment with ZnCl2 ameliorated the Px-induced decrease in hippocampal neurogenesis and cognitive impairment. These results suggest that via disruption of vesicular zinc stores in hippocampal mossy fiber terminals, chemotherapy may impinge upon one or more of the sequential stages involved in the maturation of new neurons derived via adult neurogenesis and thereby leads to the progressive cognitive decline associated with CICI.

Voluntary exercise reduces both chemotherapy-induced neuropathic nociception and deficits in hippocampal cellular proliferation in a mouse model of paclitaxel-induced peripheral neuropathy

“…Study 1). In another study (Lee et al, 2017), a more robust chronic paclitaxel dosing regimen (10 mg/kg every other day for 30 days) did not alter cellular proliferation in mice, as measured by Ki67 expression levels, suggesting that paclitaxel’s impact on hippocampal cellular proliferation may be dependent on many factors including age, species and treatment regimen. Beneficial effects of prior voluntary exercise on paclitaxel-induced neuropathic nociception may be more robust and pervasive than its protective effects against paclitaxel-induced deficits in hippocampal cell proliferation and survival, which, in our study, appear to require ongoing voluntary exercise…”

Real Time Imaging and Dynamics of Hippocampal Zn2+ under Epileptic Condition Using a Ratiometric Fluorescent Probe

“…In addition, cancer chemotherapy causes disruption of vesicular Zn 2+ stores in hippocampal mossy fiber terminals which leads to decrease in hippocampal neurogenesis. A recent study reported that the dietary Zn 2+ supplement can act as a simple alternative treatment for hippocampal neurogenesis to ameliorate Chemotherapy-induced cognitive impairment 14 . Hence, detection of Zn 2+ concentration and its dynamics in both physiological and pathological conditions pose high demand.…”

Antimicrotubule Agent-Induced Zinc Neurotoxicity

“…47,48) Our recent published work has suggested that reduced vesicular zinc is related to the CICI-induced reduction of neurogenesis and accompanying cognitive decline. 14) Our lab has demonstrated that zinc may be an essential element for hippocampal neurogenesis. Vesicular zinc is most highly localized in the hippocampal mossy fibers of dentate granule cells.…”

“…These results suggest that reduced vesicular zinc pools in hippocampal synaptic terminals by Px may interfere with neurogenesis and therefore lead to the cognitive decline seen in patients after chemotherapy. 14) Thus, we have proposed that zinc supplements can be used as a simple alternative treatment to ameliorate CICI. However, further clinical investigation in humans is needed.…”

“…[11][12][13] Since many anticancer agents are derivatives of antimicrotubule chemicals, a possible relationship between CICI and zinc-induced neuronal death has been suggested. 14) Zinc is one of the most important transition metals in our bodily functions-one of the most important elements for DNA synthesis, cell division and many other physiological functions. Most of the zinc in the neuronal cytoplasm comes in a protein-bound form.…”