A Single Dose of Atorvastatin Applied Acutely after Spinal Cord Injury Suppresses Inflammation, Apoptosis, and Promotes Axon Outgrowth, Which Might Be Essential for Favorable Functional Outcome

Abstract

The aim of our study was to limit the inflammatory response after a spinal cord injury (SCI) using Atorvastatin (ATR), a potent inhibitor of cholesterol biosynthesis. Adult Wistar rats were divided into five experimental groups: one control group, two Th9 compression (40 g/15 min) groups, and two Th9 compression + ATR (5 mg/kg, i.p.) groups. The animals survived one day and six weeks. ATR applied in a single dose immediately post-SCI strongly reduced IL-1β release at 4 and 24 h and considerably reduced the activation of resident cells at one day post-injury. Acute ATR treatment effectively prevented the excessive infiltration of destructive M1 macrophages cranially, at the lesion site, and caudally (by 66%, 62%, and 52%, respectively) one day post-injury, whereas the infiltration of beneficial M2 macrophages was less affected (by 27%, 41%, and 16%). In addition, at the same time point, ATR visibly decreased caspase-3 cleavage in neurons, astrocytes, and oligodendrocytes. Six weeks post-SCI, ATR increased the expression of neurofilaments in the dorsolateral columns and Gap43-positive fibers in the lateral columns around the epicenter, and from day 30 to 42, significantly improved the motor activity of the hindlimbs. We suggest that early modulation of the inflammatory response via effects on the M1/M2 macrophages and the inhibition of caspase-3 expression could be crucial for the functional outcome.

A review of novel trends in management of canine spinal cord injury

“…Atorvastatin, lovastatin, pravastatin, and simvastatin, drugs competitively inhibiting HMG-CoA (3-hydroxymethylglutaryl-coenzyme A) reductase, are widely used in the treatment of dyslipidaemias and prevention of atherosclerotic cardiovascular complications. They are also able to support neuronal survival and improve functional recovery after SCI (Bimbova et al 2018). The positive influence of statins on neuronal survival and restriction of TM size is mediated by activation of the Wtn/β-catenin signalling pathway, reduction of levels of inflammatory factors (such as TNF-α, and IL-1β), infiltration of SC by destructive M 1 macrophages, restriction of endothelial nitric oxide, and by inhibition of caspase-3 and caspase-9 cleavage in SC neurons, astrocytes, and oligodendrocytes (Bimbova et al 2018).…”

“…They are also able to support neuronal survival and improve functional recovery after SCI (Bimbova et al 2018). The positive influence of statins on neuronal survival and restriction of TM size is mediated by activation of the Wtn/β-catenin signalling pathway, reduction of levels of inflammatory factors (such as TNF-α, and IL-1β), infiltration of SC by destructive M 1 macrophages, restriction of endothelial nitric oxide, and by inhibition of caspase-3 and caspase-9 cleavage in SC neurons, astrocytes, and oligodendrocytes (Bimbova et al 2018). Although a long-term statin therapy can cause myopathy which may progress to rhabdomyolysis, new-onset type-2 diabetes mellitus and, probably, haemorragic stroke, the less serious adverse effects of statin therapy generally resolve rapidly when administration is terminated (Peto and Collins 2018).…”

Rhein lysinate improves motor function in rats with spinal cord injury via inhibiting p38 MAPK pathway

“…1,2 Neuronal apoptosis is an important component of secondary SCI and spinal nerve cell death after SCI is caused by apoptosis. [3][4][5] Studies in different SCI models have confirmed that neuronal apoptosis is widespread in secondary SCI. 6,7 Apoptosis, also known as programmed cell death, is an intrinsic natural physiological process that maintains the stability of various tissues in the human body by eliminating metabolites of dead cells.…”

“…Spinal cord injury (SCI) is a serious threat to human health, which includes primary and secondary injuries . Neuronal apoptosis is an important component of secondary SCI and spinal nerve cell death after SCI is caused by apoptosis . Studies in different SCI models have confirmed that neuronal apoptosis is widespread in secondary SCI .…”

Therapeutic Strategies for Spinal Cord Injury

“…Among the drugs used for other pathologies, atorvastatin (ATR)—a potent inhibitor of cholesterol biosynthesis—can modulate secondary injury, reducing Interleukin 1 (IL1), M1 macrophage infiltration, and decreasing the activity of caspase 3. These changes lead to increased sprouting and improved locomotor activity [ 5 ]. Pharmacological treatment can be combined with stem cells, but these therapies do not always have to synergize, as in the case of ependymal stem/progenitor cells combined with a pharmacological compound FM19G11, which reduced glial scar and increased the expression of Olig1 in vivo, but did not lead to greater behavioral improvement when compared with the individual treatments [ 6 ].…”