Minocycline Reduces the Severity of Autonomic Dysreflexia after Experimental Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is a devastating neurological condition for which there is no effective treatment to restore neurological function. The development of new treatments for those with SCI may be hampered by the insensitivity of clinical tools to assess motor function in humans. Treatments aimed at preserving neuronal function through anti-inflammatory pathways (i.e., neuroprotection) have been a mainstay of pre-clinical SCI research for decades. Minocycline, a clinically available antibiotic agent with anti-inflammatory properties, has demonstrated promising neuroprotective effects in a variety of animal models and improved motor recovery in a Phase-2 human trial. Here, we leveraged our recently developed T3 severe contusion model in the rat to determine the ability of minocycline to preserve descending sympathoexcitatory axons and improve cardiovascular control after SCI. Forty-one male Wistar rats were randomized to either a treatment group (minocycline; n = 20) or a control group (vehicle; n = 21). All rats received a severe T3 contusion. Minocycline (or vehicle) was administered intraperitoneally at one hour post-injury (90 mg/kg), then every 12 h for two weeks (45 mg/kg). Neuroanatomical correlates (lesion area, descending sympathoexcitatory axons) were assessed, in addition to an assessment of cardiovascular control (hemodynamics, autonomic dysreflexia) and motor behavior. Here, we show that minocycline reduces lesion area, increases the number of descending sympathoexctitatory axons traversing the injury site, and ultimately reduces the severity of autonomic dysreflexia. Finally, we show that autonomic dysreflexia is a more sensitive marker of treatment stratification than motor function.

Snx27 Deletion Promotes Recovery From Spinal Cord Injury by Neuroprotection and Reduces Macrophage/Microglia Proliferation

“…They can be activated to various degrees after spinal cord injury (41, 42). Although there are different functional states of macrophage/microglia activated after SCI, treatments aimed at anti-inflammatory pathways have been a mainstay of pre-clinical SCI research for many years (43). Macrophage/microglia that infiltrate in the injured area can secrete inflammatory factors such as TNFα, IL-1, IL-6, aggravating neuronal damage and cavity formation, while suppressing neurogenesis and axonal regeneration (36, 44).…”

Neuroimmune System as a Driving Force for Plasticity Following CNS Injury

“…Moreover, results from a phase II clinical trial of minocycline treatment after acute SCI demonstrate significant functional improvements in motor function (Casha et al, 2012). Coupled with recent findings that minocycline treatment preserves sympathoexcitatory axons and attenuates the severity of autonomic dysreflexia following SCI (Squair et al, 2018), the use of this immunomodulatory pharmacotherapy to modulate injury-induced plasticity exemplifies the tremendous potential of therapeutically targeting the neuroimmune system. However, further research is necessary to explore these implications on plasticity throughout the neural axis.…”

Effects of Cyclosporin-A, Minocycline, and Tacrolimus (FK506) on Enhanced Behavioral and Biochemical Recovery from Spinal Cord Injury in Rats

“…Furthermore, minocycline improves functional outcome, reduces lesion size and cell death, and alters cytokine expression after SCI [43][44][45]. Minocycline reduces the lesion area, increases the number of descending sympathoexcitatory axons traversing the injury site, and ultimately reduces the severity of autonomic dysreflexia [46]. In a murine model of SCI, minocycline treatment was superior to methylprednisolone in promoting functional improvement [44] and had neuroprotective effects on the SCI epicenter [47], motor neuron recovery, and neuropathic pain [48].…”