Repurposing approved drugs for streptozotocin-induced central nervous system impairments

Introduction

Cancer remains a life-threatening disease, with incidence increasing worldwide. Advances in early detection and treatment have improved survival; however, many anticancer therapies also damage healthy tissues and cause organ-specific and systemic toxicities, including neurotoxicity. Despite ongoing research, no approved therapy is currently available to manage chemotherapy induced cognitive impairment, reduced pain threshold, and mood disturbances, collectively referred to as chemobrain. Because anticancer drugs act through diverse and complex mechanisms, there is still no fully established experimental model for studying chemobrain. Therefore, appropriate rodent models are needed to investigate its molecular mechanisms and evaluate potential therapeutic strategies. Streptozotocin is an alkylating agent still used in contemporary oncology for selected neuroendocrine carcinomas. In rodents, it is widely used to induce diabetes for the study of diabetic neuropathic pain. Since cognitive deficits are also among its reported adverse effects, streptozotocin based models may provide a useful experimental platform to study selected mechanisms relevant to treatment related cognitive impairment.

Aims

The aim of this study was to investigate whether streptozotocin impairs central nervous system function in CD-1 mice, with a primary focus on cognition. We also evaluated the procognitive, antidepressant-like, anxiolytic-like, and antinociceptive effects of drugs already used for diabetic neuropathic pain, to assess whether they have a broader profile of action. This included pregabalin and mirogabalin, as well as duloxetine, which is used for both diabetic neuropathic pain and depression. In addition, the anti-Alzheimer’s agent rivastigmine was included to assess whether these compounds may be repurposed to alleviate central nervous system dysfunction and memory deficits.

Methods

Streptozotocin (40 mg/kg) was administered intraperitoneally once daily for 5 consecutive days. The novel object recognition test, passive avoidance test, forced swim test, four-plate test, and hot plate test were used to assess the effects of the tested compounds administered intraperitoneally at different doses for 2 weeks in a streptozotocin treated mice. Statistical analysis was performed using one way or repeated measures ANOVA followed by Dunnett’s post hoc comparison.

Results

Streptozotocin treated mice demonstrated deficits in learning and memory, as assessed by the novel object recognition and passive avoidance tests. Pregabalin (3 and 10 mg/kg) and mirogabalin (3 and 10 mg/kg) significantly increased step-through latency in the passive avoidance test. In the novel object recognition test, pregabalin (3 mg/kg), mirogabalin (10 mg/kg), and rivastigmine (1 mg/kg) significantly increased the discrimination index. In the forced swim test mirogabalin and duloxetine showed antidepressant-like properties in streptozotocin exposed mice. None of these drugs demonstrated anxiolytic-like properties. All drugs administered subchronically reduced hyperglycemia in streptozotocin treated mice and only rivastigmine had some negative impact on animals’ motor functions. These data suggest that repurposing these compounds may alleviate chemotherapy induced cognitive impairment, indicating a potential therapeutic approach for this clinical condition.

Conclusions

These findings suggest that streptozotocin based models may be used to study chemobrain and that pregabalin, mirogabalin, duloxetine and rivastigmine may attenuate streptozotocin induced chemobrain. These agents warrant further investigation as repurposed candidates for treatment related memory deficits and other symptoms of chemobrain.

References

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