Effects of Etanercept and Minocycline in a rat model of spinal cord injury

Abstract

Loss of function is usually considered the major consequence of spinal cord injury (SCI). However, pain severely compromises the quality of life in nearly 70% of SCI patients. The principal aim of this study was to assess the contribution of Tumor necrosis factor alpha (TNF-alpha) to SCI pain. TNF-alpha blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain, especially following SCI. Following T13 spinal cord hemisection, we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept, a fusion protein blocker of TNF-alpha. Immediate treatment (starting at the time of injury) with etanercept resulted in markedly reduced mechanical allodynia 1, 2, 3 and 4 weeks after SCI. Delayed treatment had no effect. Immediate etanercept treatment also reduced spinal microglial activation assessed by OX-42 immunostaining, a putative marker of activated microglia. To assess whether the effects of etanercept were mediated via decreased microglial activation, we examined the effects of the microglial inhibitor, minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment. Minocycline also significantly reduced microglial OX-42 expression. Furthermore, minocycline decreased the expression of noxious-stimulation-induced c-Fos, suggesting an effect on evoked neuronal activity. This study demonstrates that TNF-alpha plays an important role in the establishment of neuropathic pain following SCI, seemingly dependent on microglial activation. Pharmacological targeting of TNF-alpha may offer therapeutic opportunities for treating SCI pain.

Perispinal etanercept: a new therapeutic paradigm in neurology

“…In a third animal study, immediate intrathecal administration of etanercept resulted in markedly reduced mechanical allodynia 1, 2, 3 and 4 weeks after injury and reduced spinal microglial activation [149]. Treatment with etanercept that was delayed for 14 days after injury had no effect [149].…”

“…[3,4,6,10,55,56,59, 62,70,73,80,82,84,85,107,169,170] • Spinal cord injury [7,143,144,[146][147][148][149][150] • Traumatic brain injury [136] • Stroke [137][138][139][140] …”

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

“…It is known that both receptors for TNF-α are expressed in dorsal root ganglion neurons and that intra-articular injection of TNF-α blocking agents reduces nociception elicited by joint inflammation (10). TNF-α is also involved in development of mechanical hyperalgesia following injury (11,12). Hence, we hypothesized that TNF-α leads to a major change in pain perception in the CNS during arthritis.…”

Biologic TNFα-inhibitors that cross the human blood-brain barrier

“…1 In the case of the mAb drugs, both chimeric and humanized mAb's directed against TNFα are FDA approved drugs. 2 TNFα also plays a pathologic role in the central nervous system (CNS) including both acute disorders, such as stroke, 3 brain trauma 4,5 or spinal cord injury (SCI), 6 as well as chronic diseases of the brain, such as Alzheimer disease (AD) 7 or depression. 8 However, the biologic TNFIs cannot be developed as drugs for the brain, because the biologic TNFIs do not cross the blood-brain barrier (BBB).…”