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Targeting Upregulation of Neuronal IGF1/IGF1R Signalling in the Spinal Cord Prevents Cisplatin-Induced Peripheral
Chieh-Ru Fu1, Jia-Hao Chen1, Ya-Chen Yang1
1Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Background:
Chemotherapy-induced peripheral neuropathy (CIPN), characterised by a stocking-glove distribution of numbness and pain, is a severe clinical challenge. Our previous study showed that overexpression of neuronal G protein-coupled receptor kinase (GRK2) in the spinal dorsal horn (SDH) prevented cisplatin-induced CIPN in mice. The underlying mechanism, however, remains unclear. This study aimed to explore the role of insulin-like growth factor 1 (IGF1) in preventing CIPN through neuronal GRK2 in the SDH of mice.
Methods:
CIPN model was established by intraperitoneally injecting cisplatin (23 mg/kg) in mice. Neuronal IGF1R or GRK2 in SDH was downregulated by intraspinally injecting an AAV vector delivering IGF1R or GRK2 shRNA with hSyn promoter. Mechanical allodynia and sensory deficits were assessed by von Frey test and adhesive removal test. The expression of IGF1, IGF1R and Iba1 was assessed by immunostaining. Neuroinflammation was assessed by real-time PCR. The IGF1R and GRK2 levels were assessed by Western blot.
Results:
Cisplatin chemotherapy induced a decrease of IGF1 and p-IGF1R in SDH; intrathecal (i.t) injection of recombinant IGF1 (rIGF1) significantly prevented cisplatin-induced mechanical allodynia, sensory deficit, and microglia activation and neuroinflammation in SDH. IGF1R was primarily localised within neurons (~81%). Downregulation of neuronal IGF1R (AAV-shIGF1R) inhibited the preventive effect of i.t. rIGF1 on CIPN, and on the upregulation of GRK2 in SDH. Furthermore, downregulation of neuronal GRK2 in SDH inhibited the preventive effect of i.t. rIGF1 on CIPN.
Conclusions:
I.t. injection of rIGF1 regulates neuronal GRK2 through neuronal IGF1R in SDH, alleviates microglial activation and neuroinflammation, thereby preventing cisplatin-induced CIPN.
Significance Statement:
This work elucidates the role of neuronal IGF1/IGF1R in the process of CIPN prevention and provides new animal-based evidence for CIPN prevention by targeting neuronal IGF1/IGF1R in SDH.
Insights
Insulin-like growth factor 1 (IGF1) injection prevents chemotherapy-induced peripheral neuropathy (CIPN) by regulating neuronal G protein-coupled receptor kinase 2 (GRK2) in the spinal dorsal horn. This pathway alleviates neuroinflammation and sensory deficits, offering a novel therapeutic strategy for CIPN.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of cancer treatment.
- Neuronal G protein-coupled receptor kinase 2 (GRK2) overexpression in the spinal dorsal horn (SDH) previously showed protective effects against CIPN.
- The precise mechanism underlying this neuroprotection remained unclear.
Purpose of the Study:
- To investigate the role of insulin-like growth factor 1 (IGF1) in preventing CIPN.
- To explore the involvement of neuronal GRK2 in the SDH as a mediator of IGF1's protective effects against CIPN.
Main Methods:
- A mouse model of cisplatin-induced CIPN was established.
- Adeno-associated viral vectors were used to downregulate neuronal IGF1 receptor (IGF1R) or GRK2 in the SDH.
- Behavioral tests assessed mechanical allodynia and sensory deficits.
- Immunohistochemistry, real-time PCR, and Western blotting were employed to evaluate molecular changes and neuroinflammation.
Main Results:
- Cisplatin treatment reduced IGF1 and phosphorylated IGF1R (p-IGF1R) levels in the SDH.
- Intrathecal administration of recombinant IGF1 (rIGF1) reversed cisplatin-induced CIPN symptoms, microglial activation, and neuroinflammation.
- IGF1R was predominantly localized in neurons.
- Downregulation of neuronal IGF1R or GRK2 abolished the protective effects of rIGF1 against CIPN.
Conclusions:
- Intrathecal rIGF1 administration activates neuronal IGF1R, leading to GRK2 regulation in the SDH.
- This mechanism effectively alleviates microglial activation and neuroinflammation, thereby preventing cisplatin-induced CIPN.
- The study provides evidence for targeting the neuronal IGF1/IGF1R pathway in the SDH as a strategy for CIPN prevention.
