All Title Author
Keywords Abstract

PLOS ONE  2014 

Minocycline and Risperidone Prevent Microglia Activation and Rescue Behavioral Deficits Induced by Neonatal Intrahippocampal Injection of Lipopolysaccharide in Rats

DOI: 10.1371/journal.pone.0093966

Full-Text   Cite this paper   Add to My Lib


Background Various signs of activation of microglia have been reported in schizophrenia, and it is hypothesized that microglia activation is closely associated with the neuropathology of schizophrenia. Methods Neonatal intrahippocampal injection of lipopolysaccharide (LPS), an activator of microglia, was performed in rats at postnatal day 7 (P7), and they were separately given saline, risperidone (0.5 mg/kg), minocycline (40 mg/kg) or a combination of both of them at P42 for consecutive 14 days. Behavioral changes (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were examined and the number of microglia was assessed by using immunohistochemistry in adulthood. Results The adult rats in LPS-injected group showed obvious behavioral alteration (e. g. deficits in social interaction, novel object recognition and prepulse inhibition) and a dramatic increase of number of activated microglial cells in the hippocampus and other brain regions such as cerebral cortex and thalamus compared to those in saline-injected group. Interestingly, application of either minocycline, risperidone or both of them significantly rescued behavioral deficits and attenuated microglia activation. Conclusion Our results suggest that inhibition of microglia activation may be one of mechanisms underlying the antipsychotic effect of minocycline and risperidone.


[1]  Monji A, Kato TA, Mizoguchi Y, Horikawa H, Seki Y, et al. (2013) Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry 42: 115–121. doi: 10.1016/j.pnpbp.2011.12.002
[2]  Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, et al. (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63: 801–808. doi: 10.1016/j.biopsych.2007.09.024
[3]  Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55: 233–238. doi: 10.1002/glia.20459
[4]  Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119: 89–105. doi: 10.1007/s00401-009-0622-0
[5]  Bayer TA, Buslei R, Havas L, Falkai P (1999) Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 271: 126–128. doi: 10.1016/s0304-3940(99)00545-5
[6]  van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, et al. (2008) Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 64: 820–822. doi: 10.1016/j.biopsych.2008.04.025
[7]  Jhamnani K, Shivakumar V, Kalmady S, Rao NP, Venkatasubramanian G (2013) Successful use of add-on minocycline for treatment of persistent negative symptoms in schizophrenia. J Neuropsychiatry Clin Neurosci 25: E06–07. doi: 10.1176/appi.neuropsych.11120376
[8]  Van Amersfoort ES, Van Berkel TJ, Kuiper J (2003) Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev 16: 379–414. doi: 10.1128/cmr.16.3.379-414.2003
[9]  Lee SY, Kim B, Jeong HK, Min KJ, Liu T, et al. (2010) Enhanced phosphatidylinositol 4-phosphate 5-kinase alpha expression and PI(4,5)P2 production in LPS-stimulated microglia. Neurochem Int 57: 600–607. doi: 10.1016/j.neuint.2010.07.008
[10]  Feleder C, Tseng KY, Calhoon GG, O'Donnell P (2010) Neonatal intrahippocampal immune challenge alters dopamine modulation of prefrontal cortical interneurons in adult rats. Biol Psychiatry 67: 386–392. doi: 10.1016/j.biopsych.2009.09.028
[11]  Zhang L, Shirayama Y, Iyo M, Hashimoto K (2007) Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology 32: 2004–2010. doi: 10.1038/sj.npp.1301313
[12]  Fujita Y, Ishima T, Kunitachi S, Hagiwara H, Zhang L, et al. (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline. Prog Neuropsychopharmacol Biol Psychiatry 32: 336–339. doi: 10.1016/j.pnpbp.2007.08.031
[13]  Richtand NM, Ahlbrand R, Horn P, Stanford K, Bronson SL, et al. (2011) Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation. J Psychiatr Res 45: 1194–1201. doi: 10.1016/j.jpsychires.2011.02.007
[14]  Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24: 417–463. doi: 10.1016/s0149-7634(00)00014-2
[15]  Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30: 80–89. doi: 10.1038/sj.npp.1300518
[16]  Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, et al. (2008) Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology (Berl) 196: 233–241. doi: 10.1007/s00213-007-0955-0
[17]  Ratnayake U, Quinn TA, Castillo-Melendez M, Dickinson H, Walker DW (2012) Behaviour and hippocampus-specific changes in spiny mouse neonates after treatment of the mother with the viral-mimetic Poly I:C at mid-pregnancy. Brain Behav Immun 26: 1288–1299. doi: 10.1016/j.bbi.2012.08.011
[18]  Tseng KY, Chambers RA, Lipska BK (2009) The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res 204: 295–305. doi: 10.1016/j.bbr.2008.11.039
[19]  Sams-Dodd F, Lipska BK, Weinberger DR (1997) Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology (Berl) 132: 303–310. doi: 10.1007/s002130050349
[20]  Amann LC, Gandal MJ, Halene TB, Ehrlichman RS, White SL, et al. (2010) Mouse behavioral endophenotypes for schizophrenia. Brain Res Bull 83: 147–161. doi: 10.1016/j.brainresbull.2010.04.008
[21]  Radewicz K, Garey LJ, Gentleman SM, Reynolds R (2000) Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 59: 137–150.
[22]  Manitz MP, Esslinger M, Wachholz S, Plumper J, Friebe A, et al. (2013) The role of microglia during life span in neuropsychiatric disease—an animal study. Schizophr Res 143: 221–222. doi: 10.1016/j.schres.2012.10.028
[23]  Kato T, Monji A, Hashioka S, Kanba S (2007) Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res 92: 108–115. doi: 10.1016/j.schres.2007.01.019
[24]  Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, et al. (2006) Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry 30: 1381–1393. doi: 10.1016/j.pnpbp.2006.05.015
[25]  Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, et al. (2010) A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 71: 138–149. doi: 10.4088/jcp.08m04666yel
[26]  MacDowell KS, Garcia-Bueno B, Madrigal JL, Parellada M, Arango C, et al. (2013) Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation. Int J Neuropsychopharmacol 16: 121–135. doi: 10.1017/s1461145711001775
[27]  Chaves C, Marque CR, Trzesniak C, Machado de Sousa JP, Zuardi AW, et al. (2009) Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update. Braz J Med Biol Res 42: 1002–1014. doi: 10.1590/s0100-879x2009001100002
[28]  Lee M (2013) Neurotransmitters and microglial-mediated neuroinflammation. Curr Protein Pept Sci 14: 21–32. doi: 10.2174/1389203711314010005
[29]  Kato TA, Monji A, Yasukawa K, Mizoguchi Y, Horikawa H, et al. (2011) Aripiprazole inhibits superoxide generation from phorbol-myristate-acetate (PMA)-stimulated microglia in vitro: implication for antioxidative psychotropic actions via microglia. Schizophr Res 129: 172–182. doi: 10.1016/j.schres.2011.03.019


comments powered by Disqus

Contact Us


微信:OALib Journal