An intriguing way to enhance rehabilitation of grasping in rats after spinal cord injury

Rehabilitation after nervous system injury, such as spinal cord injury or stroke, can improve outcomes when undertaken in the acute or chronic phase (Ward, 2017) but it rarely restores all lost function in humans. Rehabilitation can be exhausting and the dose of rehabilitation available to each patient is also limited by its expense: adjunct therapies that enhance rehabilitation would thus be of great value. Animal studies indicate too that the effectiveness of rehabilitation declines with time since spinal cord injury. In this issue of Brain, a team led by Karim Fouad reports perhaps surprisingly and counter-intuitively, that treatment with bacterial endotoxins (lipopolysaccharides; LPS) can enhance medium or high intensity rehabilitation in rats with spinal cord injuries that occurred 2 months previously (Torres-Espı́n et al., 2018). In fact, this study is an extension of work dating back many decades that indicates that bacterial endotoxins (by themselves or in combination with other treatments) can improve anatomical and functional recovery after acute spinal cord injury (reviewed in Popovich et al., 2012). In the present study, adult rats received mid-cervical (C4) unilateral dorsolateral quadrant spinal cord injuries that persistently impaired their ability to grasp and retrieve sugar pellets with their previously-preferred paw. Eight and 11 weeks later, rats received intraperitoneal injection of saline or LPS at doses that induced effects within the cervical spinal cord (e.g. microglial activation), but induced only mild sickness for 52 days (body temperature was typically increased only 1 C). From 8 weeks, rats received either low, medium or higher doses of rehabilitation of pellet retrieval for an additional 7 or 8 weeks. The key message of the paper is that medium or high (but not low) doses of rehabilitation led to greater success in pellet retrieval in rats treated with LPS than with saline. In animals treated with LPS and high doses of rehabilitation, wrist movements during retrieval (‘supination’) were more normal; anterograde tract tracing showed increased sprouting of the injured corticospinal tract in the cervical segment rostral to the injury; and microstimulation of motor cortex evoked greater output to the contralateral (disabled) posterior forelimb muscles. So how does LPS enhance rehabilitation in rats after spinal cord injury? This is a complex question that will take many years to address adequately as we do not yet know how even an intact system reaches and grasps. But given the animal data showing that rehabilitation as a monotherapy is more efficient after acute spinal cord injury than after chronic injury, then perhaps, when given after chronic injury, LPS enhances rehabilitation by recapitulating some of the inflammatory components of the acutely injured state. Acutely, spinal cord injury generates damage associated molecular pattern molecules (DAMPs) and opens the blood–brain barrier, facilitating the influx of inflammatory peripheral cells into the injury site. Both beneficial and harmful effects have been attributed to the presence and activation of microglia, macrophages and lymphocytes. At the injury site, activated immune cells contribute to the production of cytokines, proteolytic enzymes and matrix metalloproteinases inducing a reactive process of secondary cell death, leading to increased cavitation and cyst formation, and exacerbating neurological dysfunction. Paradoxically, inflammation can also be beneficial. The effects of macrophages at the injury site depend on the balance of macrophage subtypes (often dichotomized as M1 or M2 but shown by transcriptomics to be spectral). ‘Classically activated (M1)’ macrophages are pro-inflammatory and contribute to glial scar formation and production of proinflammatory cytokines, reactive oxygen species, nitric oxide and proteolytic enzymes that lead to extracellular matrix degradation and tissue damage. ‘Alternatively activated (M2)’ macrophages are anti-inflammatory, provide neural and axonal trophic support, partially degrade the glial scar and induce inflammation resolution, thus contributing to BRAIN 2018: 141; 1888–1899 | 1888