Changes in Expression of Receptor-Interacting Protein Kinase 1 in Secondary Neural Tissue Damage Following Spinal Cord Injury

Abstract

Introduction: Necroptosis is a form of programmed cell death that is different from apoptotic cell death. Receptor-interacting protein kinase 1 (RIPK1) plays a particularly important function in necroptosis execution. This study investigated changes in expression of RIPK1 in secondary neural tissue damage following spinal cord injury in mice. The time course of the RIPK1 expression was also compared with that of apoptotic cell death in the lesion site. Methods and Materials: Immunostaining for RIPK1 was performed at different time points after spinal cord injury. The protein expressions of RIPK1 were determined by western blot. The RIPK1 expressions in various neural cells were investigated using immunohistochemistry. To investigate the time course of apoptotic cell death, TUNEL-positive cells were counted at the different time points. To compare the incidence of necroptosis and apoptosis, the RIPK1-labeled sections were co-stained with TUNEL. Results: The RIPK1 expression was significantly upregulated in the injured spinal cord. The upregulation of RIPK1 expression was observed in neurons, astrocytes, and oligodendrocytes. The increase in RIPK1 expression started at 4 hours and peaked at 3 days after injury. Time course of the RIPK1 expression was similar to that of apoptosis detected by TUNEL. Interestingly, the increased expression of RIPK1 was rarely observed in the TUNEL-positive cells. Furthermore, the number of RIPK1-positive cells was significantly higher than that of TUNEL-positive cells. Conclusions: This study demonstrated that the expression of RIPK1 increased in various neural cells and peaked at 3 days following spinal cord injury. The temporal change of the RIPK1 expression was analogous to that of apoptosis at the lesion site. However, the increase in RIPK1 expression was barely seen in the apoptotic cells. These findings suggested that the RIPK1 might contribute to the pathological mechanism of the secondary neural tissue damage after spinal cord injury.

TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats

“…Our results are in line with previous findings suggesting that upregulated RIPK1 expression may provide an essential mechanism for the pathogenesis of neuropathic pain. Increased RIPK1 expression has been observed in various types of neuropathic pain in rats harboring a spinal cord injury [ 6 , 7 ] or sciatic nerve injury [ 8 , 9 ]. Moreover, the intraperitoneal administration of Nec-1 was reported to ameliorate both mechanical allodynia and hyperalgesia in a rat model of sciatic nerve injury [ 9 ].…”

“…Recent evidence supports the involvement of RIPK1 in the processes underlying nociceptive information. RIPK1 expression significantly increases at the site of injury following a spinal cord laminectomy [ 6 ], a spinal cord injury [ 7 ], and in a chronic constriction injury model [ 8 , 9 ]. Moreover, a blockade of RIPK1 expression alleviates hyperalgesia and mechanical allodynia in rats with sciatic nerve injury [ 9 ].…”

Chaperone-Mediated Autophagy in Neurodegenerative Diseases and Acute Neurological Insults in the Central Nervous System

“…Interestingly, our results also showed that the number of LAMP2A-expressing cells increased from 24 h and peaked at 3 days, lasting for at least 7 days after injury. The time course of LAMP2A expression is similar to that of apoptosis after SCI [ 112 , 113 , 114 ]. Apoptosis is considered a major cause of secondary damage following SCI [ 112 , 114 ].…”

“…Following acute neurological insults to the CNS, including cerebral infarction, TBI and SCI, secondary injury can be induced by various molecular mechanisms, such as oxidative stress and neuroinflammation in the brain and spinal cord [ 132 , 133 ]. Such secondary injury is involved in multiple pathologies associated with neural cell death and neurodegeneration, aggravating the initial tissue damage of the CNS [ 112 , 113 , 132 ]. The secondary damage can be a potential therapeutic target for effective treatment of acute neurological insults to the CNS.…”

Role of necroptosis in traumatic brain and spinal cord injuries

“…Although TBI and SCI are capable of sharing numerous identical pathophysiology-related characteristics, the temporal patterns of RIPK1/RIPK3 and MLKL expression between SCI and TBI differ. Kanno et al investigated the time course of RIPK1 protein expression state inside impaired neural tissue after SCI and reported that the increase in RIPK1 expression was initiated at 24 h, peaked at 3 days, and continued for 7 days after SCI [58] . Interestingly, Liu et al found that unlike RIPK1, the levels of RIPK3 and MLKL protein rose markedly at 1 day but decreased by day 3 after injury [59] .…”