Article

Neuroprotective role of minocycline in co-cultures of human fetal neurons and microglia.

University of Connecticut Health Center, Department of Neuroscience, 263 Farmington Avenue, Farmington, CT 06030-3401, USA.
Experimental Neurology (Impact Factor: 4.65). 06/2008; 211(1):41-51. DOI: 10.1016/j.expneurol.2007.12.024
Source: PubMed

ABSTRACT Bacterial infections during pregnancy often result in premature birth and neonatal white matter damage. During these infections, microglia, the resident immune cells of the CNS, undergo activation and contribute to further neuronal damage of the CNS. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and protects neurons in rodents but data about its effects on human cells are limited. We studied the mechanism of the neuroprotective effect of minocycline in either purified cell cultures or co-cultures of microglia and neurons from human fetal brain during inflammation induced by lipopolysaccharide (LPS). In neuron/microglial co-cultures, minocycline treatment prevented activation and proliferation of microglia and protected neurons as demonstrated by decreased neuronal cell death and a shift of Bcl-2 family proteins toward anti-apoptotic ratio. Notably, neither minocycline nor LPS had an effect on neurons in purified neuronal cultures. The ability of minocycline to regulate activation of human fetal microglia might be relevant in therapies used towards treating neonatal CNS infections.

0 Bookmarks
 · 
60 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation. Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 μg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. Functional scoring was done at 6 hours following surgery and 12-hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly attenuated microglial activation and proinflammatory cytokine production in vitro with a greater than twofold reduction in tumor necrosis factor-α. Alpha 2a agonist, dexmedetomidine treatment at reperfusion preserved neurologic function and neuronal viability. Furthermore, dexmedetomidine treatment resulted in an attenuation of microglial activation and proinflammatory cytokine production both in vivo and in vitro following LPS stimulation. This finding lends insight into the mechanism of paralysis following thoracic aortic interventions and may guide future pharmacologic targets for attenuating spinal cord ischemia and reperfusion.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 07/2013; · 3.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background It is difficult to improve negative symptoms and cognitive impairments in schizophrenia. A previous pilot study has shown that minocycline, a semi-synthetic second-generation tetracycline, is effective in treating for negative and/or cognitive symptoms in schizophrenia. Objectives The present study was designed to examine the efficacy and safety of minocycline for the treatment of negative symptoms and cognitive impairments in patients with schizophrenia. Methods Ninety-two patients with early stage schizophrenia treated with risperidone entered this 16-week, double blind, randomized, placebo-controlled clinical trial. Subjects were randomly assigned to receive minocycline (200 mg per day) or the placebo. The primary outcome was evaluated using the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the response rate of SANS, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI), and cognitive tests. Results Subjects receiving minocycline had greater improvements on SANS total scores and PANSS negative subscale scores (P < 0.001) when compared with those receiving the placebo. Rates of treatment response (43.6%) in the minocycline group were significantly higher than those in the placebo group (10.0%) after 16 weeks of treatment. There was no significant difference between the seven cognitive domains (P > 0.05), except for the attention domain (P = 0.044). Conclusions The addition of minocycline to atypical antipsychotic drugs in early schizophrenia had significant efficacy on negative symptoms but had a slight effect on the attention domains of patients with schizophrenia. It may be considered as a new adjunct treatment for negative symptoms of schizophrenia. Clinical trials.gov identifier: NCT01493622.
    Schizophrenia Research 01/2014; · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Perinatal brain damage is one of the leading causes of life long disability. This damage could be hypoxic-ischemic, inflammatory, or both. This mini-review discusses different interventions aiming at minimizing inflammatory processes in the neonatal brain, both before and after insult. Current options of anti-inflammatory measures for neonates remain quite limited. We describe current anti-inflammatory intervention strategies such as avoiding perinatal infection and inflammation, and reducing exposure to inflammatory processes. We describe the known effects of anti-inflammatory drugs such as steroids, antibiotics, and indomethacin, and the possible anti-inflammatory role of other substances such as IL-1 receptor antagonists, erythropoietin, caffeine, estradiol, insulin-like growth factor, and melatonin as well as endogenous protectors, and genetic regulation of inflammation. If successful, these may decrease mortality and long-term morbidity among term and pre-term infants.
    Frontiers in Pediatrics 01/2014; 2:30.