Willias Masocha | Kuwait University - Health Sciences Center (original) (raw)
Papers by Willias Masocha
Brain Research, Dec 13, 2002
Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; h... more Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; however, the mechanisms involved
BMC Proceedings, 2008
Human African Trypanosomiasis (HAT) is caused by subspecies of the extracellular parasite Trypano... more Human African Trypanosomiasis (HAT) is caused by subspecies of the extracellular parasite Trypanosoma brucei. Treatment of the late meningoencephalitic stage of the disease still relies on very toxic drugs. For understanding morbidity and design of markers for better staging of HAT, studies on mechanisms by which the parasites pass across the blood-brain barrier (BBB) are important. We have previously observed that trypanosomes, similar to leukocytes, invade the brain by a multi-step process in Trypanosoma brucei brucei-infected mice. We here studied expression of chemokine transcripts in the brain using microarray and real-time PCR and related this to trafficking of trypanosomes and leukocytes across the BBB by immunohistochemistry and to morbity in chemokine and chemokine receptor gene deleted mice. At 15 days post infection (p.i.), when parasites had first invaded the brain parenchyma, CXCL10 and CCL28 transcripts were differentially up-regulated in the brain compared to 6 days p.i. More chemokine transcripts, and especially CXCL9 and 10, were differentially expressed in the brains at 28 days p.i. Expression of these transcripts was significantly reduced in infected IFN-gamma-/-mice, indicating an important role of this cytokine in their induction. Mice deficient of CXCL10 or its receptor, CXCR3, showed reduced accumulation of CD4+ and CD8+ T cells, and trypanosomes in the brain compared to WT mice, notwithstanding similar levels of parasitemia, and a compen-satory up-regulation of transcripts for the other two CXCR3 ligands, CXCL9 and 11, in infected mice. A reduced weight occurring in infected WT mice was not observed in either CXCR3-/-or CXCL10-/-infected mice. These results suggest that CXCL10/CXCR3 interaction plays a crucial role in the recruitment of T-cells into the brain parenchyma and may modulate factors involved in trypanosome brain invasion, which leads to morbidity.
BMC Proceedings, 2008
Trypanosoma brucei (T. b.) subspecies invade the brain parenchyma at late stages of human and exp... more Trypanosoma brucei (T. b.) subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. Here, we compared the outcome of infection with T. b. in MHC-matched (H2 b ) C57BL/6 (B6) and 129Sv/Ev (Sv-129). While Sv-129 showed higher parasitemia and lower specific IgM (but not IgG) antibody levels than B6 mice, the number of trypanosomes, CD4 + and CD8 + T cells in the brain parenchyma was higher in B6 mice. B6 mice lost weight and showed higher cumulative mortality compared to Sv-129 mice. Higher levels of IL-1β, IL-6, IL-10, TNF-α, IFN-γ, ICAM-1 and E-selectin, but low levels of TGF-β mRNA were present in brains of B6 compared to Sv-129-infected mice. Thus, host genetics differentially determine invasion of T. b. brucei into the brain parenchyma, which is paralleled by the severity of inflammation in the brain and course of the disease, but not by parasitemia or antibody titers.
Neglected Tropical Diseases and Conditions of the Nervous System, 2014
Physiology and Behavior, 2007
Subspecies of the extracellular parasite, Trypanosoma brucei, which are spread by the tsetse fly ... more Subspecies of the extracellular parasite, Trypanosoma brucei, which are spread by the tsetse fly in sub-Saharan Africa, cause in humans Sleeping Sickness. In experimental rodent models the parasite can at a certain stage of disease pass through the blood-brain barrier across or between the endothelial cells and the vessel basement membranes. The laminin composition of the basement membranes determines whether they are permissive to parasite penetration. One cytokine, interferon-gamma, plays an important role in regulating the trypanosome trafficking into the brain. Treatment strategies aim at developing drugs that can impede penetration of trypanosomes into the brain and/or that can eliminate trypanosomes once they are inside the brain parenchyma, but have lower toxicity than the ones presently in use.
Virulence, 2012
The blood-brain barrier (BBB) is a structural and functional barrier that protects the central ne... more The blood-brain barrier (BBB) is a structural and functional barrier that protects the central nervous system (CNS) from invasion by blood-borne pathogens including parasites. However, some intracellular and extracellular parasites can traverse the BBB during the course of infection and cause neurological disturbances and/or damage which are at times fatal. The means by which parasites cross the BBB and how the immune system controls the parasites within the brain are still unclear. In this review we present the current understanding of the processes utilized by two human neuropathogenic parasites, Trypanosoma brucei spp and Toxoplasma gondii, to go across the BBB and consequences of CNS invasion. We also describe briefly other parasites that can invade the brain and how they interact with or circumvent the BBB. The roles played by parasite-derived and host-derived molecules during parasitic and white blood cell invasion of the brain are discussed.
Handbook of Clinical Neurology, 2013
Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic in... more Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection.
Scandinavian Journal of Immunology, 2008
Trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimenta... more Trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. In this study, we compared the outcome of infection with T. b. brucei in MHC-matched (H-2b) C57BL/6 (B6) and 129Sv/Ev (Sv-129). Sv-129 showed higher parasitaemia and lower specific IgM (but not IgG) antibody levels than B6 mice. The number of trypanosomes, CD4+ and CD8+ T cells in the brain parenchyma was higher in B6 mice. B6 mice lost weight and showed higher cumulative mortality when compared with Sv-129 mice. Higher levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma, ICAM-1 and E-selectin, but low levels of TGF-beta mRNA were present in brains of B6 when compared with Sv-129-infected mice. Thus, host genetics differentially determine the invasion of T. b. brucei into the brain parenchyma, which is paralleled by the severity of inflammation in the brain and course of the disease, but not by parasitaemia nor by antibody titres.
PLoS ONE, 2013
Microglia activation results in release of proinflammatory molecules including cytokines, which c... more Microglia activation results in release of proinflammatory molecules including cytokines, which contribute to neuronal damage in the central nervous system (CNS) if not controlled. Tetracycline antibiotics such as minocycline inhibit microglial activation and cytokine expression during CNS inflammation. In the present study we found that administration of chemically modified tetracycline-3 (COL-3), inhibits lipopolysaccharide (LPS)-induced microglial and p38 MAPK activation, as well as the increase in TNF-α, but not IL-1β expression, in the brains of BALB/c mice. COL-3 has been described to have no antibacterial activity. We observed that COL-3 had no activity against a Gram-negative bacteria, Escherichia coli; however surprisingly, COL-3 had antibacterial activity against a Gram-positive bacteria Staphylococcus aureus, with a minimum inhibitory concentration of 1 mg/ml. Our data show that COL-3 has some antibacterial activity against S. aureus, inhibits LPS-induced neuroinflammation, and displays potential as a therapeutic agent for treatment of conditions involving CNS inflammation.
Medical Principles and Practice, 2013
To study the potential of chemically modified tetracycline-3 (COL-3), a potent matrix metalloprot... more To study the potential of chemically modified tetracycline-3 (COL-3), a potent matrix metalloproteinase (MMP) inhibitor, to protect against the development of paclitaxel-induced painful neuropathy and its immunomodulatory effects. The reaction latency to thermal stimuli (hot plate test) of female BALB/c mice was recorded before and after treatment with paclitaxel (2 mg/kg i.p.), paclitaxel plus COL-3 (4, 20 or 40 mg/kg p.o.) or their vehicles for 5 consecutive days. Gene transcripts of CD11b (marker for microglia), 5 cytokines (IFN-γ, IL-1β, IL-6, IL-10 and TNF-α) and 3 chemokines (CCL2, CXCL10 and CX3CL1) were quantified by real-time PCR in the brains, spinal cords and spleens of mice sacrificed on day 7 after treatment. Treatment with paclitaxel reduced the reaction latency time to thermal stimuli (thermal hyperalgesia) for 4 weeks, with maximum effect on days 7 and 10. The coadministration of paclitaxel with COL-3 40 mg/kg, but not lower doses, prevented the development of paclitaxel-induced thermal hyperalgesia. Treatment with paclitaxel alone or coadministration with COL-3 increased CD11b transcript levels in the brain but not in the spinal cord. Treatment with paclitaxel reduced IL-6 transcript levels in the spinal cord but did not alter the transcript levels of other cytokines or chemokines in the brain, spinal cord or spleen. The coadministration of COL-3 with paclitaxel significantly increased the transcript levels of IL-6 in the spleen and decreased CX3CL1 transcripts in the brain in comparison to treatment with paclitaxel alone. Our results indicate that the MMP inhibitor COL-3 protected against paclitaxel-induced thermal hyperalgesia and, thus, could be useful in the prevention of chemotherapy-induced painful neuropathy.
Life Sciences, 2009
We evaluated the possibility of using the video-based Catwalk gait analysis method to measure wei... more We evaluated the possibility of using the video-based Catwalk gait analysis method to measure weight bearing changes and for testing pharmacological antinociception in freely moving mice with lipopolysaccharide (LPS)-induced monoarthritis. Main methods: LPS or its solvent (PBS) was injected intra-articularly into the right hind (RH) limb ankle joint through the Achilles tendon of C57BL/6 mice. The Catwalk system was used to assess behavioral changes in freely moving mice. The effects of indomethacin on changes in LPS-inoculated mice were examined. Key findings: Mice inoculated with LPS into the RH limb showed reduced paw pressure (measured as light intensity) and print area on the RH limb, whereas they exerted more pressure with the left hind (LH) and front limbs, showing a transfer of weight bearing from RH to LH and front limbs, which was significant at 2 days post-LPS inoculation. There were no differences between the front limbs. No changes were observed in the PBS injected controls. There were no changes in interlimb coordination (regularity index) in both PBS-and LPS-injected mice. Treatment with indomethacin (10 and 100 mg/kg) restored the weight bearing (measured as the ratio of the pressure exerted by the paws) and the print area ratios of LPS-inoculated mice similar to that observed in control mice.
![Research paper thumbnail of Corrigendum to “Assessment of weight bearing changes and pharmacological antinociception in mice with LPS-induced monoarthritis using the Catwalk gait analysis system” [Life Sciences 85 (2009) 462–469]](https://attachments.academia-assets.com/43713420/thumbnails/1.jpg)
](Life Sciences, 2009
Corrigendum to "Assessment of weight bearing changes and pharmacological antinociception in mice ... more Corrigendum to "Assessment of weight bearing changes and pharmacological antinociception in mice with LPS-induced monoarthritis using the Catwalk gait analysis system" [Life Sciences 85 (2009) 462-469]
Journal of Pharmacology and Experimental Therapeutics, 2003
We evaluated the modulation by Na+,K+-ATPase inhibitors of morphine-induced antinociception in th... more We evaluated the modulation by Na+,K+-ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [3H]naloxone binding to forebrain membranes. The antinociception induced by morphine (1-32 mg/kg, s.c.) in mice was dose-dependently antagonized by ouabain (1-10 ng/mouse, i.c.v.), which produced a significant shift to the right of the morphine dose-response curve. The i.c.v. administration of three Na+,K+-ATPase inhibitors (ouabain at 0.1-100, digoxin at 1-1000, and digitoxin at 10-10000 ng/mouse) dose-dependently antagonized the antinociceptive effect of morphine (4 mg/kg, s.c.) in mice, with the following order of potency: ouabain > digoxin > digitoxin. This effect cannot be explained by any interaction at opioid receptors, since none of these Na+,K+-ATPase inhibitors displaced [3H]naloxone from its binding sites, whereas naloxone did so in a concentration-dependent manner. The antinociception induced by morphine (5 mg/kg, s.c.) in rats was antagonized by the i.c.v. administration of ouabain at 10 ng/rat, whereas it was not significantly modified by intrathecally administered ouabain (10 and 100 ng/rat). These results suggest that the activation of Na+,K+-ATPase plays a role in the supraspinal, but not spinal, antinociceptive effect of morphine.
Journal of Neuroimmunology, 2009
LPS activates microglia, which are normally maintained in a quiescent state by CD200-CD200 recept... more LPS activates microglia, which are normally maintained in a quiescent state by CD200-CD200 receptor (CD200R) interaction. MAC-1 (a microglia marker) mRNA expression was increased in mice brains up to 1 year post LPS administration (i.p.). Minocycline treatment did not prevent LPS (5 mg/kg)-induced increase in MAC-1 mRNA but reduced that induced by 0.1 mg/kg LPS. CD200R mRNA decreased starting at 4 h, whereas CD200 mRNA increased at 4 h and decreased at 1 year post LPS inoculation. Thus, LPS-induced changes in CD200-CD200R equilibrium might keep microglia chronically activated. Minocycline does not effectively inhibit microglia activation induced by high-dose LPS.
Journal of Neuroimmunology, 2010
Infection with Trypanosoma brucei, which causes African trypanosomiasis, activates microglia, whi... more Infection with Trypanosoma brucei, which causes African trypanosomiasis, activates microglia, which are constitutively maintained in a quiescent state through CD200-CD200 receptor interactions. C57BL/6 mice have one inhibitory receptor, CD200R and three activating members, CD200 receptor-like (RL)a-c. Infection increased MAC-1 (microglia marker), CD200RLa and CD200RLb, but not CD200, CD200R or CD200RLc, transcript levels in the brains. Minocycline treatment inhibited the infection-induced elevation of MAC-1 and CD200RLa transcripts, but had no significant effect on CD200 or the other receptors. This suggests that CD200RLa might play a role in microglia/macrophage activation during trypanosome infection.
The Journal of Infectious Diseases, 2009
Background. Human African trypanosomiasis, caused by Trypanosoma brucei, involves an early hemoly... more Background. Human African trypanosomiasis, caused by Trypanosoma brucei, involves an early hemolymphatic stage followed by a late encephalitic stage.
The Journal of Infectious Diseases, 2005
There is an urgent need to discontinue the use of highly toxic compounds still in use for treatme... more There is an urgent need to discontinue the use of highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We show here that intraperitoneal injection of the adenosine analogue cordycepin (3 -deoxyadenosine), together with an adenosine deaminase (ADA) inhibitor (coformycin or deoxycoformycin), cures Trypanosoma brucei brucei infection in mice. Treatment was also effective at a stage when the trypanosomes had penetrated into the brain parenchyma, as determined by double immunolabeling of parasites and cerebral vessel endothelial cells in brain sections. At this stage, the parasites were eliminated not only from the blood but also from the brain parenchyma. In parallel with the elimination of parasites, in treated mice, the number of CD45 + inflammatory cells in the brain parenchyma was reduced. Treatment was not immunosuppressive. In vitro incubation with cordycepin reduced the growth of T. brucei brucei and T. cruzi, as well as Leishmania major and L. amazonensis. Administration of cordycepin plus deoxycofomycin to T. cruzi-infected mice also significantly reduced parasitemia. Accordingly, we propose nucleoside analogues resistant to ADA as candidates for treatment of late-stage HAT.
Journal of Clinical Investigation, 2004
Brain Research, 2002
Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; h... more Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; however, the mechanisms involved
Brain Research, Dec 13, 2002
Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; h... more Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; however, the mechanisms involved
BMC Proceedings, 2008
Human African Trypanosomiasis (HAT) is caused by subspecies of the extracellular parasite Trypano... more Human African Trypanosomiasis (HAT) is caused by subspecies of the extracellular parasite Trypanosoma brucei. Treatment of the late meningoencephalitic stage of the disease still relies on very toxic drugs. For understanding morbidity and design of markers for better staging of HAT, studies on mechanisms by which the parasites pass across the blood-brain barrier (BBB) are important. We have previously observed that trypanosomes, similar to leukocytes, invade the brain by a multi-step process in Trypanosoma brucei brucei-infected mice. We here studied expression of chemokine transcripts in the brain using microarray and real-time PCR and related this to trafficking of trypanosomes and leukocytes across the BBB by immunohistochemistry and to morbity in chemokine and chemokine receptor gene deleted mice. At 15 days post infection (p.i.), when parasites had first invaded the brain parenchyma, CXCL10 and CCL28 transcripts were differentially up-regulated in the brain compared to 6 days p.i. More chemokine transcripts, and especially CXCL9 and 10, were differentially expressed in the brains at 28 days p.i. Expression of these transcripts was significantly reduced in infected IFN-gamma-/-mice, indicating an important role of this cytokine in their induction. Mice deficient of CXCL10 or its receptor, CXCR3, showed reduced accumulation of CD4+ and CD8+ T cells, and trypanosomes in the brain compared to WT mice, notwithstanding similar levels of parasitemia, and a compen-satory up-regulation of transcripts for the other two CXCR3 ligands, CXCL9 and 11, in infected mice. A reduced weight occurring in infected WT mice was not observed in either CXCR3-/-or CXCL10-/-infected mice. These results suggest that CXCL10/CXCR3 interaction plays a crucial role in the recruitment of T-cells into the brain parenchyma and may modulate factors involved in trypanosome brain invasion, which leads to morbidity.
BMC Proceedings, 2008
Trypanosoma brucei (T. b.) subspecies invade the brain parenchyma at late stages of human and exp... more Trypanosoma brucei (T. b.) subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. Here, we compared the outcome of infection with T. b. in MHC-matched (H2 b ) C57BL/6 (B6) and 129Sv/Ev (Sv-129). While Sv-129 showed higher parasitemia and lower specific IgM (but not IgG) antibody levels than B6 mice, the number of trypanosomes, CD4 + and CD8 + T cells in the brain parenchyma was higher in B6 mice. B6 mice lost weight and showed higher cumulative mortality compared to Sv-129 mice. Higher levels of IL-1β, IL-6, IL-10, TNF-α, IFN-γ, ICAM-1 and E-selectin, but low levels of TGF-β mRNA were present in brains of B6 compared to Sv-129-infected mice. Thus, host genetics differentially determine invasion of T. b. brucei into the brain parenchyma, which is paralleled by the severity of inflammation in the brain and course of the disease, but not by parasitemia or antibody titers.
Neglected Tropical Diseases and Conditions of the Nervous System, 2014
Physiology and Behavior, 2007
Subspecies of the extracellular parasite, Trypanosoma brucei, which are spread by the tsetse fly ... more Subspecies of the extracellular parasite, Trypanosoma brucei, which are spread by the tsetse fly in sub-Saharan Africa, cause in humans Sleeping Sickness. In experimental rodent models the parasite can at a certain stage of disease pass through the blood-brain barrier across or between the endothelial cells and the vessel basement membranes. The laminin composition of the basement membranes determines whether they are permissive to parasite penetration. One cytokine, interferon-gamma, plays an important role in regulating the trypanosome trafficking into the brain. Treatment strategies aim at developing drugs that can impede penetration of trypanosomes into the brain and/or that can eliminate trypanosomes once they are inside the brain parenchyma, but have lower toxicity than the ones presently in use.
Virulence, 2012
The blood-brain barrier (BBB) is a structural and functional barrier that protects the central ne... more The blood-brain barrier (BBB) is a structural and functional barrier that protects the central nervous system (CNS) from invasion by blood-borne pathogens including parasites. However, some intracellular and extracellular parasites can traverse the BBB during the course of infection and cause neurological disturbances and/or damage which are at times fatal. The means by which parasites cross the BBB and how the immune system controls the parasites within the brain are still unclear. In this review we present the current understanding of the processes utilized by two human neuropathogenic parasites, Trypanosoma brucei spp and Toxoplasma gondii, to go across the BBB and consequences of CNS invasion. We also describe briefly other parasites that can invade the brain and how they interact with or circumvent the BBB. The roles played by parasite-derived and host-derived molecules during parasitic and white blood cell invasion of the brain are discussed.
Handbook of Clinical Neurology, 2013
Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic in... more Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection.
Scandinavian Journal of Immunology, 2008
Trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimenta... more Trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. In this study, we compared the outcome of infection with T. b. brucei in MHC-matched (H-2b) C57BL/6 (B6) and 129Sv/Ev (Sv-129). Sv-129 showed higher parasitaemia and lower specific IgM (but not IgG) antibody levels than B6 mice. The number of trypanosomes, CD4+ and CD8+ T cells in the brain parenchyma was higher in B6 mice. B6 mice lost weight and showed higher cumulative mortality when compared with Sv-129 mice. Higher levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma, ICAM-1 and E-selectin, but low levels of TGF-beta mRNA were present in brains of B6 when compared with Sv-129-infected mice. Thus, host genetics differentially determine the invasion of T. b. brucei into the brain parenchyma, which is paralleled by the severity of inflammation in the brain and course of the disease, but not by parasitaemia nor by antibody titres.
PLoS ONE, 2013
Microglia activation results in release of proinflammatory molecules including cytokines, which c... more Microglia activation results in release of proinflammatory molecules including cytokines, which contribute to neuronal damage in the central nervous system (CNS) if not controlled. Tetracycline antibiotics such as minocycline inhibit microglial activation and cytokine expression during CNS inflammation. In the present study we found that administration of chemically modified tetracycline-3 (COL-3), inhibits lipopolysaccharide (LPS)-induced microglial and p38 MAPK activation, as well as the increase in TNF-α, but not IL-1β expression, in the brains of BALB/c mice. COL-3 has been described to have no antibacterial activity. We observed that COL-3 had no activity against a Gram-negative bacteria, Escherichia coli; however surprisingly, COL-3 had antibacterial activity against a Gram-positive bacteria Staphylococcus aureus, with a minimum inhibitory concentration of 1 mg/ml. Our data show that COL-3 has some antibacterial activity against S. aureus, inhibits LPS-induced neuroinflammation, and displays potential as a therapeutic agent for treatment of conditions involving CNS inflammation.
Medical Principles and Practice, 2013
To study the potential of chemically modified tetracycline-3 (COL-3), a potent matrix metalloprot... more To study the potential of chemically modified tetracycline-3 (COL-3), a potent matrix metalloproteinase (MMP) inhibitor, to protect against the development of paclitaxel-induced painful neuropathy and its immunomodulatory effects. The reaction latency to thermal stimuli (hot plate test) of female BALB/c mice was recorded before and after treatment with paclitaxel (2 mg/kg i.p.), paclitaxel plus COL-3 (4, 20 or 40 mg/kg p.o.) or their vehicles for 5 consecutive days. Gene transcripts of CD11b (marker for microglia), 5 cytokines (IFN-γ, IL-1β, IL-6, IL-10 and TNF-α) and 3 chemokines (CCL2, CXCL10 and CX3CL1) were quantified by real-time PCR in the brains, spinal cords and spleens of mice sacrificed on day 7 after treatment. Treatment with paclitaxel reduced the reaction latency time to thermal stimuli (thermal hyperalgesia) for 4 weeks, with maximum effect on days 7 and 10. The coadministration of paclitaxel with COL-3 40 mg/kg, but not lower doses, prevented the development of paclitaxel-induced thermal hyperalgesia. Treatment with paclitaxel alone or coadministration with COL-3 increased CD11b transcript levels in the brain but not in the spinal cord. Treatment with paclitaxel reduced IL-6 transcript levels in the spinal cord but did not alter the transcript levels of other cytokines or chemokines in the brain, spinal cord or spleen. The coadministration of COL-3 with paclitaxel significantly increased the transcript levels of IL-6 in the spleen and decreased CX3CL1 transcripts in the brain in comparison to treatment with paclitaxel alone. Our results indicate that the MMP inhibitor COL-3 protected against paclitaxel-induced thermal hyperalgesia and, thus, could be useful in the prevention of chemotherapy-induced painful neuropathy.
Life Sciences, 2009
We evaluated the possibility of using the video-based Catwalk gait analysis method to measure wei... more We evaluated the possibility of using the video-based Catwalk gait analysis method to measure weight bearing changes and for testing pharmacological antinociception in freely moving mice with lipopolysaccharide (LPS)-induced monoarthritis. Main methods: LPS or its solvent (PBS) was injected intra-articularly into the right hind (RH) limb ankle joint through the Achilles tendon of C57BL/6 mice. The Catwalk system was used to assess behavioral changes in freely moving mice. The effects of indomethacin on changes in LPS-inoculated mice were examined. Key findings: Mice inoculated with LPS into the RH limb showed reduced paw pressure (measured as light intensity) and print area on the RH limb, whereas they exerted more pressure with the left hind (LH) and front limbs, showing a transfer of weight bearing from RH to LH and front limbs, which was significant at 2 days post-LPS inoculation. There were no differences between the front limbs. No changes were observed in the PBS injected controls. There were no changes in interlimb coordination (regularity index) in both PBS-and LPS-injected mice. Treatment with indomethacin (10 and 100 mg/kg) restored the weight bearing (measured as the ratio of the pressure exerted by the paws) and the print area ratios of LPS-inoculated mice similar to that observed in control mice.
Life Sciences, 2009
Corrigendum to "Assessment of weight bearing changes and pharmacological antinociception in mice ... more Corrigendum to "Assessment of weight bearing changes and pharmacological antinociception in mice with LPS-induced monoarthritis using the Catwalk gait analysis system" [Life Sciences 85 (2009) 462-469]
Journal of Pharmacology and Experimental Therapeutics, 2003
We evaluated the modulation by Na+,K+-ATPase inhibitors of morphine-induced antinociception in th... more We evaluated the modulation by Na+,K+-ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [3H]naloxone binding to forebrain membranes. The antinociception induced by morphine (1-32 mg/kg, s.c.) in mice was dose-dependently antagonized by ouabain (1-10 ng/mouse, i.c.v.), which produced a significant shift to the right of the morphine dose-response curve. The i.c.v. administration of three Na+,K+-ATPase inhibitors (ouabain at 0.1-100, digoxin at 1-1000, and digitoxin at 10-10000 ng/mouse) dose-dependently antagonized the antinociceptive effect of morphine (4 mg/kg, s.c.) in mice, with the following order of potency: ouabain > digoxin > digitoxin. This effect cannot be explained by any interaction at opioid receptors, since none of these Na+,K+-ATPase inhibitors displaced [3H]naloxone from its binding sites, whereas naloxone did so in a concentration-dependent manner. The antinociception induced by morphine (5 mg/kg, s.c.) in rats was antagonized by the i.c.v. administration of ouabain at 10 ng/rat, whereas it was not significantly modified by intrathecally administered ouabain (10 and 100 ng/rat). These results suggest that the activation of Na+,K+-ATPase plays a role in the supraspinal, but not spinal, antinociceptive effect of morphine.
Journal of Neuroimmunology, 2009
LPS activates microglia, which are normally maintained in a quiescent state by CD200-CD200 recept... more LPS activates microglia, which are normally maintained in a quiescent state by CD200-CD200 receptor (CD200R) interaction. MAC-1 (a microglia marker) mRNA expression was increased in mice brains up to 1 year post LPS administration (i.p.). Minocycline treatment did not prevent LPS (5 mg/kg)-induced increase in MAC-1 mRNA but reduced that induced by 0.1 mg/kg LPS. CD200R mRNA decreased starting at 4 h, whereas CD200 mRNA increased at 4 h and decreased at 1 year post LPS inoculation. Thus, LPS-induced changes in CD200-CD200R equilibrium might keep microglia chronically activated. Minocycline does not effectively inhibit microglia activation induced by high-dose LPS.
Journal of Neuroimmunology, 2010
Infection with Trypanosoma brucei, which causes African trypanosomiasis, activates microglia, whi... more Infection with Trypanosoma brucei, which causes African trypanosomiasis, activates microglia, which are constitutively maintained in a quiescent state through CD200-CD200 receptor interactions. C57BL/6 mice have one inhibitory receptor, CD200R and three activating members, CD200 receptor-like (RL)a-c. Infection increased MAC-1 (microglia marker), CD200RLa and CD200RLb, but not CD200, CD200R or CD200RLc, transcript levels in the brains. Minocycline treatment inhibited the infection-induced elevation of MAC-1 and CD200RLa transcripts, but had no significant effect on CD200 or the other receptors. This suggests that CD200RLa might play a role in microglia/macrophage activation during trypanosome infection.
The Journal of Infectious Diseases, 2009
Background. Human African trypanosomiasis, caused by Trypanosoma brucei, involves an early hemoly... more Background. Human African trypanosomiasis, caused by Trypanosoma brucei, involves an early hemolymphatic stage followed by a late encephalitic stage.
The Journal of Infectious Diseases, 2005
There is an urgent need to discontinue the use of highly toxic compounds still in use for treatme... more There is an urgent need to discontinue the use of highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We show here that intraperitoneal injection of the adenosine analogue cordycepin (3 -deoxyadenosine), together with an adenosine deaminase (ADA) inhibitor (coformycin or deoxycoformycin), cures Trypanosoma brucei brucei infection in mice. Treatment was also effective at a stage when the trypanosomes had penetrated into the brain parenchyma, as determined by double immunolabeling of parasites and cerebral vessel endothelial cells in brain sections. At this stage, the parasites were eliminated not only from the blood but also from the brain parenchyma. In parallel with the elimination of parasites, in treated mice, the number of CD45 + inflammatory cells in the brain parenchyma was reduced. Treatment was not immunosuppressive. In vitro incubation with cordycepin reduced the growth of T. brucei brucei and T. cruzi, as well as Leishmania major and L. amazonensis. Administration of cordycepin plus deoxycofomycin to T. cruzi-infected mice also significantly reduced parasitemia. Accordingly, we propose nucleoside analogues resistant to ADA as candidates for treatment of late-stage HAT.
Journal of Clinical Investigation, 2004
Brain Research, 2002
Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; h... more Morphine through m-opioid receptors and G proteins modulates several cellular effector systems; however, the mechanisms involved