Abstract
Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4–L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.
Highlights
Traumatic spinal cord injury affects several thousand people worldwide every year and the main reasons are motor vehicle accidents and falls [1]
This study is the first demonstration of the neuroprotective efficacy of NAC and ALC treatments to reduce the degeneration of spinal motoneurons, and restore the density of dendritic branches and axonal terminals in the ventral horn of the hemisected spinal cord
The antioxidants tested do not affect astrocytes, they significantly attenuate the reaction of activated microglial cells
Summary
Traumatic spinal cord injury affects several thousand people worldwide every year and the main reasons are motor vehicle accidents and falls [1]. The mortality after spinal cord injury is nearly 50% and about 15–20% of the patients surviving the initial trauma will die later in hospital [2]. In the acute phase of spinal cord injury, the initial mechanical trauma damages the blood-brain barrier and neuronal tracts resulting in interruptions of blood flow, edema, hemorrhage and retrograde reaction in axotomized neurons. Pro-inflammatory cytokines, glutamate and reactive oxygen species such as peroxynitrite and superoxide radicals are produced in the injured spinal cord tissue leading to axonal swelling, myelin breakdown, inflammation and mitochondrial dysfunction followed by apoptotic death of neurons and glial cells [3,4,5,6]. Free radicals and nitric oxide generated by microglia stimulate astrocytes to secrete growth-inhibitory proteoglycans forming the astroglial scar [7] and effectively blocking axonal regeneration across the lesion site [8,9]
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