Theranostics 2021; 11(7):3109-3130. doi:10.7150/thno.53474

Research Paper

Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits

Jenolyn F. Alexander1, Alexandre V. Seua1, Luis D. Arroyo1, Pradipta R. Ray2, Andi Wangzhou2, Laura Heiβ-Lückemann3, Manfred Schedlowski3, Theodore J. Price2, Annemieke Kavelaars1, Cobi J. Heijnen1✉

1. Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States.
2. School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States.
3. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

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Citation:
Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heiβ-Lückemann L, Schedlowski M, Price TJ, Kavelaars A, Heijnen CJ. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics 2021; 11(7):3109-3130. doi:10.7150/thno.53474. Available from https://www.thno.org/v11p3109.htm

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Abstract

Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits.

Methods: Puzzle box, novel object place recognition and Y-maze tests were used to assess the cognitive function of mice. Immunofluorescence and high-resolution confocal microscopy were employed to trace the nasally delivered mitochondria and evaluate their effect on synaptic loss. Black Gold II immunostaining was used to determine myelin integrity. Transmission electron microscopy helped determine mitochondrial and membrane integrity of brain synaptosomes. RNA-sequencing was performed to analyse the hippocampal transcriptome.

Results: Two nasal administrations of mitochondria isolated from human mesenchymal stem cells to mice, restored executive functioning, working and spatial memory. Confocal imaging revealed nasally delivered mitochondria rapidly arrived in the meninges where they were readily internalized by macrophages. The administered mitochondria also accessed the rostral migratory stream and various other brain regions including the hippocampus where they colocalized with GFAP+ cells. The restoration of cognitive function was associated with structural repair of myelin in the cingulate cortex and synaptic loss in the hippocampus. Nasal mitochondrial donation also reversed the underlying synaptosomal mitochondrial defects. Moreover, transcriptome analysis by RNA-sequencing showed reversal of cisplatin-induced changes in the expression of about seven hundred genes in the hippocampus. Pathway analysis identified Nrf2-mediated response as the top canonical pathway.

Conclusion: Our results provide key evidence on the therapeutic potential of isolated mitochondria - restoring both brain structure and function, their capability to enter brain meninges and parenchyma upon nasal delivery and undergo rapid cellular internalization and alter the hippocampal transcriptome. Our data identify nasal administration of mitochondria as an effective strategy for reversing chemotherapy-induced cognitive deficits and restoring brain health, providing promise for the growing population of both adult and pediatric cancer survivors.

Keywords: chemobrain, mitochondria, nasal delivery, nrf2, mesenchymal stem cell