minocycline and Paralysis

To identify the minocycline anti-inflammatory and antiapoptotic mechanisms through which it is believed to exert spinal cord protection during aortic occlusion in the rabbit model.. An animal model of aortic occlusion-related spinal cord ischemia. Randomized study with a control group and pre-ischemia and post-ischemia escalating doses of minocycline to high-dose minocycline in the presence of either hyperglycemia, a pro-apoptotic maneuver, or wortmannin, a specific phosphatidylinositol 3-kinase antagonist.. Tertiary medical center and school of medicine laboratory.. Laboratory animals-rabbits.. Balloon obstruction of infrarenal aorta introduced via femoral artery incision.. Severe hindlimb paralysis (mean Tarlov score 0.36±0.81 out of 3) was observed in all the control group animals (9 of 11 with paraplegia and 2 of 11 with paraparesis) compared with 11 of 12 neurologically intact animals (mean Tarlov score 2.58±0.90 [p = 0.001 compared with control]) in the high-dose minocycline group. This protective effect was observed partially during a state of hyperglycemia and was completely abrogated by wortmannin. Minocycline administration resulted in higher neurologic scores (p = 0.003) and a shift to viable neurons and more apoptotic-stained nuclei resulting from reduced necrosis (p = 0.001).. In a rabbit model of infrarenal aortic occlusion, minocycline effectively reduced paraplegia by increasing the number of viable neurons in a dose-dependent manner. Its action was completely abrogated by inhibiting the phosphatidylinositol 3-kinase pathway and was inhibited partially by the pro-apoptotic hyperglycemia maneuver, indicating that the activation of cell salvage pathways and mitochondrial sites are possible targets of minocycline action in an ischemic spinal cord.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Aorta, Thoracic; Apoptosis; Balloon Occlusion; Dose-Response Relationship, Drug; Femoral Artery; Hindlimb; Male; Minocycline; Neurons; Paralysis; Rabbits; Spinal Cord Ischemia; Wortmannin

This study was initiated due to an NIH "Facilities of Research--Spinal Cord Injury" contract to support independent replication of published studies that could be considered for a clinical trial in time. Minocycline has been shown to have neuroprotective effects in models of central nervous system injury, including in a contusive spinal cord injury (SCI) model at the thoracic level. Beneficial effects of minocycline treatment included a significant improvement in locomotor behavior and reduced histopathological changes [Lee, S.M., Yune, T.Y., Kim, S.J., Park, D.O.W., Lee, Y.K., Kim, Y.C., Oh, Y.J., Markelonis, G.J., Oh, T.H., 2003. Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma. 20, 1017-1027.] To verify these important observations, we repeated this study in our laboratory. The NYU (MASCIS) Impactor was used to produce a moderate cord lesion at the vertebral level T9-T10 (height 12.5 mm, weight 10 g), (n=45), followed by administration of minocycline, 90 mg/kg (group 1: minocycline IP, n=15; group 2: minocycline IV, n=15; group 3: vehicle IP, n=8; group 4: vehicle IV, n=7) immediately after surgery and followed by two more doses of 45 mg/kg/IP at 12 h and 24 h. Open field locomotion (BBB) and subscores were examined up to 6 weeks after SCI and cords were processed for quantitative histopathological analysis. Administration of minocycline after SCI did not lead to significant behavioral or histopathological improvement. Although positive effects with minocycline have been reported in several animal models of injury with different drug administration schemes, the use of minocycline following contusive SCI requires further investigation before clinical trials are implemented.

Topics: Animals; Disease Models, Animal; Efferent Pathways; Lameness, Animal; Male; Minocycline; Motor Activity; Neuroprotective Agents; Paralysis; Rats; Rats, Sprague-Dawley; Recovery of Function; Reproducibility of Results; Spinal Cord; Spinal Cord Injuries; Thoracic Vertebrae; Treatment Failure

Systemic treatment with the tetracycline derivative, minocycline, attenuates neurologic deficits in animal models of amyotrophic lateral sclerosis, hypoxic-ischemic brain injury, and multiple sclerosis. Inhibition of microglial activation within the CNS is 1 mechanism proposed to underlie the beneficial effects of the drug in these systems. Given the widening scope of acute viral encephalitis caused by mosquito-borne pathogens, we investigated the therapeutic effects of minocycline in a murine model of fatal alphavirus encephalomyelitis in which widespread microglial activation is known to occur. We found that minocycline conferred significant protection against both paralysis and death, even when started after viral challenge and despite having no effect on CNS virus replication or spread. Further studies demonstrated that minocycline inhibited early virus-induced microglial activation and that diminished CNS production of the inflammatory mediator, interleukin (IL)-1beta, contributed to its protective effect. Therapeutic blockade of IL-1 receptors also conferred significant protection in our model, validating the importance of the IL-1 pathway in disease pathogenesis. We propose that interventions targeting detrimental host immune responses arising from activated microglia may be of benefit in humans with acute viral encephalitis caused by related mosquito-borne pathogens. Such treatments could conceivably act through neuroprotective rather than antiviral mechanisms to generate these clinical effects.

Topics: Administration, Intranasal; Alphavirus Infections; Animals; Brain; Central Nervous System; Disease Susceptibility; Encephalitis; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-1beta; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neurons; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Paralysis; Sindbis Virus; Spinal Cord; Viral Load; Virus Replication

Neuroadapted Sindbis virus (NSV) is a neurotropic virus capable of inducing the death of spinal motor neurons in mice and rats. In this study we investigated the mechanisms that underlie NSV-induced motor neuron death. We found that many degenerating spinal motor neurons were not infected directly with NSV, suggesting that bystander cell death occurs. An excitotoxic mechanism was confirmed when blockade of calcium-permeable AMPA receptors attenuated motor neuron death both in vitro and in vivo. Blockade of astroglial glutamate reuptake potentiated NSV-induced motor neuron loss in vivo, suggesting that astrocyte-mediated removal of perisynaptic glutamate is important in limiting NSV-induced excitotoxic injury. Astroglial glutamate transport was reduced markedly in the spinal cord during NSV infection, in advance of motor neuron injury in susceptible mice. In contrast, we found 5.6-fold elevated glutamate uptake in the spinal cords of mice resistant to NSV-induced paralysis. Likewise, minocycline markedly increased spinal cord glutamate transport and protected mice from NSV-induced motor neuron death. These studies suggest that NSV infection triggers a cascade of events in the spinal cord resulting in impaired astrocytic glutamate transport and excitotoxic injury of motor neurons mediated via calcium-permeable AMPA receptors. Similar changes may occur in other motor neuron disorders such as amyotrophic lateral sclerosis or West Nile Virus-induced poliomyelitis, suggesting a common tissue injury pathway.

Topics: Alphavirus Infections; Animals; Astrocytes; Biological Transport; Cell Death; Coculture Techniques; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Minocycline; Motor Neurons; Neuroprotective Agents; Paralysis; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, AMPA; Sindbis Virus; Spinal Cord

We describe an easy, minimal, rapid, and reproducible model of mouse spinal cord injury (SCI) that results in permanent paralysis involving one hind limb. We used this model to evaluate whether the paralysis can be prevented using two known neuroprotective drugs, namely leukemia inhibitory factor (LIF) and minocycline (MIN). Mice in the control vehicle (VEH) and MIN groups with SCI had negligible recovery of locomotor behavior. In contrast, the LIF groups showed a statistically significant improvement in locomotor behavior. Maximal recovery was observed when LIF was administered 2, 8, and 24 h after lesion, while no significant recovery was observed when LIF treatment commenced 1 week after the lesion. Unbiased stereological estimates revealed significantly higher numbers of myelinated axons below the lesion in the maximal recovery LIF groups. We conclude that LIF may be a useful treatment for recovery from paralysis after SCI.

Topics: Animals; Axons; Disease Models, Animal; Female; Interleukin-6; Leukemia Inhibitory Factor; Male; Mice; Minocycline; Motor Activity; Nerve Regeneration; Neuroprotective Agents; Paralysis; Recovery of Function; Spinal Cord Injuries; Time Factors

A case is reported of a young girl who developed benign intracranial hypertension, with severe bilateral papiledema and a left sixth cranial nerve palsy, after minocylcine therapy. This drug is a semisynthetic tetracycline which has proven to pass into the CSF more effectively and to have a greater lipoid solubility than the other antibiotics of the same group.

Topics: Abducens Nerve; Adolescent; Female; Humans; Intracranial Pressure; Minocycline; Papilledema; Paralysis; Pseudotumor Cerebri; Tetracyclines