Does Nrf2 Gene Transfer Facilitate Recovery After Contusion Spinal Cord Injury?

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) modulates gene expression in response to oxidative damage in neurodegenerative diseases, including spinal cord injury (SCI). We noticed that activation of Nrf2 pathway persists for an extended time after clinically relevant contusion model of SCI. Injured Nrf2(-/-) mice were impaired in hindlimb function, exhibited increased atrophy, demyelination, and astrogliosis of the SC concomitant with altered expression of genes controlling apoptosis, inflammation, and neurotrophic factors suggesting the importance of Nrf2 for recovery. We used lentiviral gene transfer to increase Nrf2 expression and improve functional recovery after SCI. Although the transferred Nrf2 was expressed in neurons and astrocytes, we noticed hindlimb function impairment and elevated expression of pro-inflammatory cytokines as an adverse effect. These toxic effects were not reduced by including Nrf2 in the lentiviral vector. Augmenting the amount of delivered Nrf2 gene diminished toxic effects of the lentivirus, yet was not sufficient to improve functional recovery. Results of this study lead to the hypothesis that Nrf2 plays a crucial and multifaceted role in recovery from SCI, but even high overexpression of Nrf2 in injured SC may not offer extra benefit, providing protection only against lentivirus-induced toxicity that is manifested in the SC.

Applications of the Keap1–Nrf2 system for gene and cell therapy

“…One of the main factors responsible for the diminished recovery of motor functions after SCI is demyelination, resulting from the delayed apoptotic death of oligodendrocytes [99] . In line with this, ablation of the Nrf2 gene results in increased demyelination after SCI [97] and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis [100] . Furthermore, Nrf2-deficient mice exhibit aggravated astrocyte activation [97] .…”

“…Mice having Nrf2 deficiency exhibit consistent impairment in locomotor functions after compression [95,98] and contusion SCI [97] . One of the main factors responsible for the diminished recovery of motor functions after SCI is demyelination, resulting from the delayed apoptotic death of oligodendrocytes [99] .…”

“…95,96] . Furthermore, utilizing a mouse contusion model we recently showed that the induction of Nrf2 is sustained, lasting at least 42 days, and forms a delayed peak at 7 days after injury [97] . These observations suggest that enhancement of the Keap1-Nrf2-ARE pathway is not restricted to acute and subacute SCI, but is also implicated in the chronic phase of recovery.…”

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

“…Overexpression of NRF2 in stem cell models of ALS showed a benefit, though in vivo delivery was too inefficient to allow an interpretation of effectiveness in vivo (25). Similarly, studies using a lentivirus encoding NRF2 in a mouse model of acute spinal cord injury were inconclusive due to deleterious effects of the lentivirus itself (19). Nonetheless, the occurrence of oxidative damage in these conditions warrants further investigation of the effectiveness of NRF2 overexpression.…”

“…Both groups of antioxidant genes have been proposed as therapeutic candidates, e.g., for neurodegenerative disorders, diabetic complications, and cardiovascular diseases, with the hope that the enzymes would be more specific, generating fewer side effects than chemical antioxidants, and that the TFs would provide a broad defense by activating hundreds of genes (15)(16)(17). However, only a few studies have been conducted to test this therapeutic strategy by gene delivery via viral vectors in animal models in vivo (18)(19)(20)(21)(22)(23)(24)(25), and no studies have compared the effectiveness of the enzymes versus the TFs, or NRF2 versus PGC1a.…”