Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis

Abstract

The mechanism by which spinal cord injury (SCI) induces neuronal death has not been thoroughly understood. Investigation on the molecular signal pathways involved in SCI-mediated neuronal apoptosis is important for development of new therapeutics for SCI. In the current study, we explore the role of heme oxygenase-1 (HO-1) in the modulation of mixed lineage kinase 3/mitogen-activated protein kinase kinase/cJUN N-terminal kinase 3 (MLK3/MKK7/JNK3) signaling, which is a pro-apoptotic pathway, after SCI. We found that MLK3/MKK7/JNK3 signaling was activated by SCI in a time-dependent manner, demonstrated by increase in activating phosphorylation of MLK3, MKK7, and JNK3. SCI also induced HO-1 expression. Administration of HO-1-expressing adeno-associated virus before SCI introduced expression of exogenous HO-1 in injured spinal cords. Exogenous HO-1 reduced phosphorylation of MLK3, MKK7, and JNK3. Consistent with its inhibitory effect on MLK3/MKK7/JNK3 signaling, exogenous HO-1 decreased SCI-induced neuronal apoptosis and improved neurological score. Further, we found that exogenous HO-1 inhibited expression of cell division cycle 42 (Cdc42), which is crucial for MLK3 activation. In vitro experiments indicated that Cdc42 was essential for neuronal apoptosis, while transduction of neurons with HO-1-expressing adeno-associated virus significantly reduced neuronal apoptosis to enhance neuronal survival. Therefore, our study disclosed a novel mechanism by which HO-1 exerted its neuroprotective efficacy. Our discovery might be valuable for developing a new therapeutic approach for SCI.

Carbon monoxide releasing molecule-3 alleviates neuron death after spinal cord injury via inflammasome regulation

“…Heme oxygenase (HO) is a highly conserved enzyme involved in the secondary injury process, it degrades heme into biliverdin, carbon monoxide, and free iron (Fe 3+ ). Genetic or pharmacological upregulation of HO-1 activity preserves spinal cord function and restrains the neuron death after SCI [ [8] , [9] , [10] , [11] , [12] , [13] ]. As a heme degradation product, carbon monoxide (CO) has been proved to have various bioactivity such as anti-inflammatory, anti-apoptotic and antioxidant in low concentration [ [14] , [15] , [16] ], which might explains the HO-1-induced protection following SCI.…”

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

“…In fact, JNK3 has been implicated in several neurodegenerative diseases, both acute and chronic. JNK3 activation has a key role in triggering apoptosis [ 91 ] and neuronal death in several neurodegenerative disorders [ 92 , 93 ]. In addition, recently it has been shown that JNK3 regulates “synaptopathy” [ 94 , 95 , 96 ], which is the first degenerative event of the excitatory synapses that leads to a phase of “spine dysfunction/injury” common to many brain diseases.…”

Treatment With 2-BFI Attenuated Spinal Cord Injury by Inhibiting Oxidative Stress and Neuronal Apoptosis via the Nrf2 Signaling Pathway

“…Normal cellular functions are controlled by cells by maintaining the oxidant and antioxidant balance. In response to oxidative stress, Nrf2 induces not only the expression of a number of antioxidant genes but also the activity of various antioxidant enzymes, such as HO-1, SOD, and GPx (Wang et al, 2012;Lin et al, 2017;Wei et al, 2018). As an indicator and regulator of oxidative stress, the Nrf2/HO-1 signaling pathway has been demonstrated to play a substantial role in protecting against oxidative stress for many years (Gan and Johnson, 2014;Freitas et al, 2015;Lu et al, 2018;Wei et al, 2018).…”

“…Heme oxygenase-1 (HO-1) is known as an endogenous antioxidative enzyme in the injured spinal cord. Several studies have shown that HO-1 is sustained in traumatic SCI (Lin et al, 2016(Lin et al, , 2017Lee et al, 2017). Furthermore, HO-1 was found to stabilize the blood-spinal cord barrier and limit oxidative stress and white matter damage in the acutely injured murine spinal cord (Lin et al, 2007).…”