Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury

Abstract

Minocycline, a clinically used tetracycline for over 40 years, crosses the blood-brain barrier and prevents caspase up-regulation. It reduces apoptosis in mouse models of Huntington's disease and familial amyotrophic lateral sclerosis (ALS) and is in clinical trial for sporadic ALS. Because apoptosis also occurs after brain and spinal cord (SCI) injury, its prevention may be useful in improving recovery. We analyzed minocycline's neuroprotective effects over 28 days following contusion SCI and found significant functional recovery compared to tetracycline. Histology, immunocytochemistry, and image analysis indicated statistically significant tissue sparing, reduced apoptosis and microgliosis, and less activated caspase-3 and substrate cleavage. Since our original report in abstract form, others have published both positive and negative effects of minocycline in various rodent models of SCI and with various routes of administration. We have since found decreased tumor necrosis factor-a, as well as caspase-3 mRNA expression, as possible mechanisms of action for minocycline's ameliorative action. These results support reports that modulating apoptosis, caspases, and microglia provide promising therapeutic targets for prevention and/or limiting the degree of functional loss after CNS trauma. Minocycline, and more potent chemically synthesized tetracyclines, may find a place in the therapeutic arsenal to promote recovery early after SCI in humans. Keywords: apoptosis, caspase inhibition, locomotor rating score, tetracycline. Spinal cord injury (SCI) in the United States is one of the leading causes of disability, with approximately 10 000 new cases reported each year (Price et al. 1994). As most new patients are young, and few reparative treatments are available, victims of this devastating condition are often incapacitated for life. The degree of dysfunction after SCI depends on several central factors, including the severity of injury and the location of the damage in the cord. Several groups, including our own, have identified a therapeutic 'window of opportunity' for strategies directed at preventing or lessening tissue loss. Other contributing factors, such as host responses and expression of stress response genes, indicate that few if any SCIs are alike, and similarly, no one treatment is expected to be universally effective. However, it is likely that early intervention will spare the maximum amount of tissue and cells, should produce the minimum degree of deficit, and result in the greatest amount of functional recovery.

The Effect of Minocycline on Motor Neuron Recovery and Neuropathic Pain in a Rat Model of Spinal Cord Injury

“…In the present study, we used an animal model of thoracic spinal cord injury to better characterize the effect of minocycline on neuroglial activation, both at the primary injury site and additional caudal levels. Consecutive rostral-caudal spreading of secondary lesion was commonly asymmetrical, with the extent of cavitation at post-injury day 28 greater caudally than rostrally 10) . With regard to potential SCI therapies in humans, animals treated with minocycline exhibited an improved recovery of motor function after hemisection.…”

“…Furthermore, these authors also demonstrated that minocycline both inhibited the expression of p75 neurotrophin receptors and the activation of Ras homolog gene family member A (RhoA) after SCI. More recently, Festoff et al reported that minocycline also might exert a neuroprotective effect in SCI by reducing microgliosis and inhibiting caspase expression 10) . In combination, this emerging data suggests that minocycline may protect the spinal cord from secondary damage after SCI via several unique pharmacologic mechanisms.…”

“…Effective against both gram-positive and -negative infections, minocycline-like all tetracycline-class antibiotics-inhibits protein synthesis at the ribosomal level 1) . In addition to this antimicrobial activity, minocycline has also been reported to exert neuroprotective effects in various experimental models of neurologic injury, including cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, kainic acid treatment, Huntington' disease, multiple sclerosis and Alzheimer' s disease 10,11,33) . Very recently, minocycline has also been suggested for use in the treatment of SCIs.…”

Current Therapeutic Approaches in Spinal Cord Injury: Pharmacological, Rehabilitation, Cell-based, and Psychological Intervention

“…Caspases are proteases involved in apoptosis, necrosis, and inflammation (Eldadah et al, 2000). After administration of minocycline, a significant decrease in caspase-3 and apoptosis was seen in moderate contusion SCI in rats (Festoff et al, 2006). Additionally, in another contusion model of SCI in rats, inhibitiory action of oxidative stress was observed following minocycline administration, specifically lipid peroxidation (Sonmez et al, 2013).…”

The executioners sing a new song: killer caspases activate microglia

“…Indeed, neuroprotection by minocycline has been observed in various animal models of PD, HD, ALS, MS, cerebral ischemia, spinal cord injury and traumatic brain injury. 85,95,96 The precise mechanism of minocycline's neuroprotective effects remains unclear. It is known, however, that minocycline is a potent inhibitor of caspase-related apoptotic pathways.…”