Nimodipine protects Schwann and neuronal cells from cell death induced by cisplatin without affecting cancer cells – Nature

Report on the Neuroprotective Effects of Nimodipine in Cisplatin Chemotherapy: Emphasizing Sustainable Development Goals

Abstract

Cisplatin is a widely used chemotherapeutic agent for solid tumors but is associated with neurotoxicity and peripheral neuropathy, adversely affecting patients’ quality of life. This study investigates the neuroprotective effects of nimodipine on cisplatin-treated Schwann cells, neuronal cells, and tumor cells. Nimodipine pre-treatment reduced cisplatin-induced cytotoxicity by up to 23.6% in neuronal cells and 30.6% in Schwann cells, without decreasing apoptosis in cancer cells. Activation of anti-apoptotic signaling pathways was observed in neuronal and Schwann cells but not in tumor cells. These findings suggest nimodipine as a promising approach to mitigate neurotoxic side effects during cisplatin chemotherapy, aligning with Sustainable Development Goal (SDG) 3: Good Health and Well-being.

Introduction

Nimodipine (NIMO), a calcium channel antagonist, primarily targets L-type voltage-gated calcium channels, exerting vasodilatory effects and neuroprotection. Initially developed for hypertension, nimodipine is now used to prevent vasospasms after aneurysmal subarachnoid hemorrhages due to its cerebrospinal fluid penetrability.

Recent studies have demonstrated nimodipine’s neuroprotective effects on neuronal, Schwann, and auditory cells, mediated by activation of anti-apoptotic pathways such as AKT and CREB phosphorylation. Cisplatin (CIS), despite its efficacy against various solid tumors, induces neurotoxicity through calcium homeostasis disruption, mitochondrial dysfunction, and reactive oxygen species (ROS) generation, leading to chemotherapy-induced peripheral neuropathy (CIPN), hearing loss, and nephrotoxicity.

This study aims to evaluate nimodipine’s protective effects against cisplatin-induced cytotoxicity in neuronal and Schwann cells and assess whether nimodipine affects tumor cells, contributing to SDG 3 by improving patient quality of life and treatment outcomes.

Materials and Methods

Cell Lines

• Neuronal cell line RN33B (rat neurons)
• Schwann cell line SW10 (mouse Schwann cells)
• Human cancer cell lines: A549 (non-small cell lung cancer), SAS (tongue squamous cell carcinoma), SKOV-3 (ovarian cancer)

Cells were cultured under standard conditions with appropriate media and supplements.

Treatment Protocols

• Pre-treatment with nimodipine (10 µM and 20 µM) 24 hours prior to cisplatin application
• Cisplatin treatment at 10 µM and 20 µM concentrations
• Control groups received solvent (ethanol) without nimodipine

Assessment Methods

• Cell death quantified by lactate dehydrogenase (LDH) activity and propidium iodide staining
• Protein analysis via Western blot for LIM-domain only four protein (LMO4), AKT, and CREB phosphorylation
• Microscopic imaging for morphological evaluation and viability assessment
• Statistical analysis using one-way ANOVA and Tukey’s multiple comparison test

Results

Neuroprotective Effect of Nimodipine

Nimodipine pre-treatment significantly decreased cisplatin-induced cell death in Schwann cells and neuronal cells:

• Reduction in cell death rate by up to 30.6% in Schwann cells and 23.6% in neuronal cells after 24 hours of cisplatin exposure
• Morphological analysis confirmed increased cell viability and reduced apoptotic features with nimodipine pre-treatment
• Activation of anti-apoptotic signaling pathways (phosphorylation of AKT and CREB) was enhanced in nimodipine-treated neuronal and Schwann cells
• Upregulation of LMO4 protein levels was observed, contributing to neuroprotection

Effect on Cancer Cells

Nimodipine did not confer protection to cancer cell lines; instead, a tendency towards increased cisplatin-induced cytotoxicity was observed, particularly in SKOV-3 ovarian cancer cells:

• No significant reduction in apoptosis in A549, SAS, and SKOV-3 cells with nimodipine pre-treatment
• Increased cell death rate in SKOV-3 cells with combined nimodipine and cisplatin treatment
• No activation of anti-apoptotic pathways by nimodipine in cancer cells; some evidence of reduced AKT and CREB phosphorylation
• LMO4 protein levels decreased with cisplatin treatment and were not restored by nimodipine in cancer cells

Discussion

The findings highlight nimodipine’s potential as a neuroprotective agent during cisplatin chemotherapy, mitigating neurotoxicity without compromising anti-cancer efficacy. This aligns with SDG 3 by promoting good health and well-being through improved cancer treatment tolerability and patient quality of life.

Nimodipine’s mechanism involves modulation of calcium influx, preventing calcium overload-induced apoptosis in neuronal cells. Its lipophilic nature allows central nervous system penetration, enhancing neuroprotection. The differential effect on tumor cells suggests nimodipine does not protect cancer cells, potentially even increasing their susceptibility to cisplatin, which supports SDG 9: Industry, Innovation, and Infrastructure by encouraging development of innovative therapeutic strategies.

Further research is needed to optimize nimodipine dosing, administration routes, and to explore its protective effects on other cisplatin-induced toxicities such as nephrotoxicity, contributing to SDG 3 and SDG 12: Responsible Consumption and Production by improving chemotherapy safety profiles.

Conclusions

Nimodipine pre-treatment effectively protects neuronal and Schwann cells from cisplatin-induced cytotoxicity through activation of anti-apoptotic pathways and upregulation of LMO4, without diminishing cisplatin’s cytotoxic effect on cancer cells. This strategy has the potential to reduce chemotherapy-associated neurotoxicity, enhancing patient quality of life and treatment outcomes, thereby supporting the achievement of Sustainable Development Goals related to health and innovation.

Implications for Sustainable Development Goals (SDGs)

• SDG 3: Good Health and Well-being – By reducing neurotoxic side effects of chemotherapy, nimodipine contributes to improved health outcomes and quality of life for cancer patients.
• SDG 9: Industry, Innovation, and Infrastructure – The study promotes innovative therapeutic approaches that enhance cancer treatment efficacy and safety.
• SDG 12: Responsible Consumption and Production – Optimizing chemotherapy regimens with neuroprotective agents like nimodipine may reduce adverse effects and resource use associated with managing side effects.

Data Availability

All data supporting the findings are included within the manuscript and supplementary materials. Further inquiries can be directed to the corresponding author.

1. Sustainable Development Goals (SDGs) Addressed or Connected to the Issues Highlighted in the Article

1. SDG 3: Good Health and Well-being
   • The article focuses on improving the quality of life for cancer patients undergoing cisplatin chemotherapy by reducing neurotoxicity and peripheral neuropathy.
   • It discusses neuroprotection, mitigation of side effects, and enhancement of chemotherapy efficacy.
2. SDG 9: Industry, Innovation and Infrastructure
   • The study involves innovative pharmaceutical research on nimodipine as a protective agent during chemotherapy.
   • It contributes to the development of new therapeutic strategies and drug repositioning.
3. SDG 10: Reduced Inequalities
   • By aiming to reduce side effects of chemotherapy, the research supports equitable access to better cancer treatment outcomes and quality of life.

2. Specific Targets Under Those SDGs Identified Based on the Article’s Content

1. SDG 3: Good Health and Well-being
   • Target 3.4: Reduce premature mortality from non-communicable diseases through prevention and treatment.
   • Target 3.8: Achieve universal health coverage, including access to quality essential health-care services and medicines.
   • Target 3.b: Support research and development of vaccines and medicines for communicable and non-communicable diseases.
2. SDG 9: Industry, Innovation and Infrastructure
   • Target 9.5: Enhance scientific research, upgrade technological capabilities, and encourage innovation in health-related fields.
3. SDG 10: Reduced Inequalities
   • Target 10.2: Empower and promote the social, economic and political inclusion of all, including those with health challenges.

3. Indicators Mentioned or Implied in the Article to Measure Progress Towards the Identified Targets

1. Indicators for SDG 3 Targets:
   • Reduction in incidence and severity of chemotherapy-induced peripheral neuropathy (CIPN) and neurotoxicity.
   • Measurement of cell death rates in neuronal and Schwann cells under cisplatin treatment with and without nimodipine pre-treatment (e.g., lactate dehydrogenase activity, propidium iodide staining).
   • Activation levels of anti-apoptotic signaling pathways (phosphorylation of AKT and CREB proteins) as molecular markers of neuroprotection.
   • Upregulation of transcription regulator LMO4 protein levels as an indicator of protective effect.
   • Clinical outcomes such as improved quality of life and reduced side effects in patients undergoing chemotherapy (implied).
2. Indicators for SDG 9 Targets:
   • Number and efficacy of innovative therapeutic agents developed or repurposed (e.g., nimodipine’s neuroprotective role in chemotherapy).
   • Scientific publications and experimental validation of new treatment mechanisms.
3. Indicators for SDG 10 Targets:
   • Access to improved chemotherapy regimens that reduce adverse effects, enhancing equitable health outcomes.
   • Patient compliance and tolerability of adjunct therapies (implied).

4. Table of SDGs, Targets, and Indicators Relevant to the Article

SDGs	Targets	Indicators
SDG 3: Good Health and Well-being	3.4: Reduce premature mortality from non-communicable diseases. 3.8: Achieve universal health coverage. 3.b: Support research and development of medicines.	Reduction in chemotherapy-induced neurotoxicity and peripheral neuropathy incidence. Cell death rate measurements (LDH activity, PI staining) in neuronal and Schwann cells. Phosphorylation levels of AKT and CREB proteins. LMO4 protein expression levels. Improved patient quality of life (implied).
SDG 9: Industry, Innovation and Infrastructure	9.5: Enhance scientific research and innovation in health.	Development and validation of nimodipine as a neuroprotective agent in chemotherapy. Scientific publications and experimental evidence supporting new therapies.
SDG 10: Reduced Inequalities	10.2: Promote inclusion of all, including those with health challenges.	Access to improved chemotherapy regimens with reduced side effects. Patient compliance and tolerability of adjunct treatments (implied).

Source: nature.com