Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits

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.

Intranasal delivery of mitochondria for treatment of Parkinson’s Disease model rats lesioned with 6-hydroxydopamine

“…We suggest that functional support of nigral DA neuron nerve terminals is more important in ST than in SN in PD therapy, because consistently higher expression level of delivered MSCs were observed in lesioned ST than in lesioned SN more than 6 months after treatment ended 10 . The latest article published in the period of our article being reviewed supports indirectly our finding that nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits 28 . ST and its cortical connections is well-known critical regulator for cognitive symptoms 29 .…”

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice

“…The protective effects of A 3 AR agonists in models of ischemic or traumatic brain injury and neuropathic pain have been attributed to suppression of neuroinflammation [ 5 , 10 , 14 , 52 ]. However, our current and previous transcriptomic analysis using RT-PCR of select genes or unbiased RNA seq approaches did not identify signs of inflammation in the brain of mice treated with cisplatin as determined by RNA seq analysis or qRT-PCR during and immediately after cisplatin treatment, or after completion of behavioral analysis [ 1 , 7 , 9 ]. Moreover, we did not detect morphological changes in astrocytes or microglia during and after cisplatin treatment [ 6 , 57 ].…”

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

“…Cisplatin mouse models have been used to investigate pharmacokinetics and tissue distribution of cisplatin [15][16][17], the repair capacity of cisplatin-DNA adducts [18], the molecular mechanisms of cisplatin toxicity [19][20][21][22][23] and to test a new generation of platinumbased chemotherapy drugs or adjunctive therapies [24][25][26][27][28][29][30][31][32][33][34][35], or other potential agents or strategies to prevent or treat cisplatin toxicities [36][37][38][39][40][41].…”

“…The proteins that participate in the NER mechanism are imported into the mitochondria in response to oxidative stress [172]. Thus, it is possible, that the NER mechanism is indeed involved in mitochondrial dysfunction (not only in DRG neurons but also in other tissues with high amounts of mitochondria like proximal tubular cells [19] and the brain [41]). However, the contribution of NER in mitochondrial dysfunction remains to be determined.…”