Epidemiological studies have reported associations between exposure to ambient particulate matter... more Epidemiological studies have reported associations between exposure to ambient particulate matter (PM) and neurocognitive impairments. Children are particularly vulnerable to the effects of PM since their CNS is still in development, especially in regions related to executive functions (EFs). Toxicological studies have reported oxidative stress and neuroinflammatory responses in mice exposed to different types of PM. However, most studies have focused on prenatal, perinatal, and adult PM exposures. The goal of this study was to assess if PM exposure impairs the postnatal development of EF. We hypothesized that exposure to diesel exhaust particles (DEP) will impair EFs by inducing inflammatory responses in the CNS and lungs. To test this hypothesis, female and male C57BL/6J mice (n=14/group) were exposed intranasally to either saline or increasing doses of DEP during postnatal days (PND) 25 to 33. General cognitive abilities and executive function were evaluated on PND 36–38 with the Puzzle Box paradigm. Mice were euthanized on PND 39 and the tissue was collected to measure the concentration of proinflammatory cytokines in the CNS and assess inflammatory cell influx into the lungs. In the brain, the levels of IL-6 and GM-CSF, but not TNFα, significantly increased in a dose-dependent manner. In the lungs, a dose-dependent influx of inflammatory cells was also observed. The results showed that mice exposed to DEP had concomitant deficits in cognitive processes related to executive functions and inflammatory responses in the brain and lungs. This suggest that DEP induced pro-inflammatory responses might be associated with deficitis in the postnatal development of EFs. In the future, the role of microglia activation will be explored. Supported by Puerto Rico IDeA Network of Biomedical Research Excellence 5P20GM103475-18.
Cervical cancer (CC) is women’s fourth most common cancer worldwide. A worrying increase in CC ra... more Cervical cancer (CC) is women’s fourth most common cancer worldwide. A worrying increase in CC rates in Hispanics suggests that besides Human Papillomaviruses infections, there may be other biological causes promoting the disease. We hypothesized that the cervical microbiome and the epithelial microenvironment favoring inflammation is conducive to disease progression. There is a lack of studies examining the part played by microbial populations in the development of precancerous lesions into cancer in Hispanic women. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation in Hispanic women living in PR while considering cervical neoplasia and HPV infection. Cervical samples collected from 91 participants coming to clinics in San Juan, underwent 16S rRNA genes (V4 region) profiling, and cytokines were measured using Luminex MAGPIX technology. Cytokines were grouped as inflammatory (IL-1β, TNFα, IFNγ, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1...
Recent studies suggest that the cervical microbiome can strongly influence inflammation and pre-c... more Recent studies suggest that the cervical microbiome can strongly influence inflammation and pre-cancerous lesion progression. However, research focused on understanding the role of microbial communities in the progression of pre-cancerous lesions to cancer in Latino women is scarce. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation while considering cervical neoplasia and HPV infection in Puerto Rican women. We collected cervical swabs and lavages from 142 participants coming to colposcopy clinics in San Juan, Puerto Rico. Genomic DNA was extracted from swabs, and 16S rDNA V4 region genes were amplified and sequenced by Illumina MiSeq. Inflammatory (IL-1β, TNFa, IFNg, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1), and trafficking (IL-8, MIP1a, MCP1, IP10) cytokines were measured from cervical lavages, using Luminex MAGPIX technology. Cytokines were related to microbes via an inflammation scoring index based on the quartile and tercile di...
Parasitic helminths and helminth-derived molecules have demonstrated to possess powerful anti-inf... more Parasitic helminths and helminth-derived molecules have demonstrated to possess powerful anti-inflammatory properties and confirmed therapeutic effects on inflammatory diseases. The helminth Fasciola hepatica has been reported to suppress specific Th1 specific immune responses induced by concurrent bacterial infections, thus demonstrating its anti-inflammatory ability in vivo. In this study, we demonstrate that native F. hepatica glutathione S-transferase (nFhGST), a major parasite excretory-secretory antigen, majorly comprised of Mu-class GST isoforms, significantly suppresses the LPS-induced TNFα and IL1β of mouse bone-marrow derived macrophages in vitro and the pro-inflammatory cytokine/chemokine storm within C57BL/6 mice exposed to lethal doses of LPS increasing their survival rate by more than 85%. Using THP1-Blue CD14 cells, a human monocyte cell line, we also demonstrate that nFhGST suppresses NF-κB activation in response to multiple TLR-ligands, including whole bacteria clin...
Exposure to airborne particulate matter (PM) has been associated with the transcriptional up-regu... more Exposure to airborne particulate matter (PM) has been associated with the transcriptional up-regulation of pro-inflammatory mediators. However, the effect of PM on post-transcriptional regulation of pro-inflammatory mediators has not been fully explored. In this study, we examined the acute effect of organic extracts from urban PM, rural PM and diesel exhaust particles (DEP) on the post-transcriptional control of interleukin-6 (IL-6) and interleukin-8 (CXCL8) using a human bronchial epithelial cell line. Both PM and DEP extracts induced the release of IL-6 and CXCL8 after 24 h of exposure. Time-course experiments were conducted to examine changes in mRNA steady-state levels and half-lives. The steady-state levels of CXCL8 mRNA increase at 15 min on cells exposed to both PM and DEP extracts. Meanwhile only the urban extract induced significant increases of IL-6 mRNA levels at 15 min. Indirect measurements of IL-6 mRNA half-life showed a dramatic increase in cells exposed to the organ...
Epidemiological studies have reported associations between exposure to ambient particulate matter... more Epidemiological studies have reported associations between exposure to ambient particulate matter (PM) and neurocognitive impairments. Children are particularly vulnerable to the effects of PM since their CNS is still in development, especially in regions related to executive functions (EFs). Toxicological studies have reported oxidative stress and neuroinflammatory responses in mice exposed to different types of PM. However, most studies have focused on prenatal, perinatal, and adult PM exposures. The goal of this study was to assess if PM exposure impairs the postnatal development of EF. We hypothesized that exposure to diesel exhaust particles (DEP) will impair EFs by inducing inflammatory responses in the CNS and lungs. To test this hypothesis, female and male C57BL/6J mice (n=14/group) were exposed intranasally to either saline or increasing doses of DEP during postnatal days (PND) 25 to 33. General cognitive abilities and executive function were evaluated on PND 36–38 with the...
Dengue (DENV) and Zika (ZIKV) are flaviviruses that co-circulate throughout the tropical and subt... more Dengue (DENV) and Zika (ZIKV) are flaviviruses that co-circulate throughout the tropical and subtropical regions. The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection. We show that CD4+ depletion in DENV-primed animals followed by ZIKV-DENV resulted in delayed viremia followed by increased viral replication in tertiary infections and dysregulated adaptive immune responses compared to ZIKV-primed animals followed by DENV-DENV infections. We show a delay in DENV-specific IgM/IgG antibody titers and neutralization in the DENV-primed CD4-depleted animals but not in ZIKV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in viremia control and priming of early and robust neutralizing antibody respon...
Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States ... more Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects have been attributed to the persistent inflammatory cascade.
The determination of the dose of inhaled aerosol particles in animal subjects is not a trivial ex... more The determination of the dose of inhaled aerosol particles in animal subjects is not a trivial exercise. In its simplest form, the dose is the amount (particle number, mass, or other relevant metric) that deposits in the respiratory tract. The amount deposited will depend on the aerosol particle sizes (e.g. the aerodynamic diameter size distribution), the duration of exposure, the exposure system's delivery efficiency, the subject's ventilation rate, the species and strain, and other factors. Similarly, species differences in the clearance rates of deposited particles will influence the time integrated particle doses. In practice, particle doses are estimated using mathematical models, previous experimental dosimetry data, tracers of the inhaled particles, and biomarkers of exposure. With care, desired aerosol doses can be achieved and documented.
Conclusions CAPs or particle-free air for 5 hours a day, 5 days per week, for a period of 6 month... more Conclusions CAPs or particle-free air for 5 hours a day, 5 days per week, for a period of 6 months. The whole-body inhalation exposures were conducted in two urban cities (Seattle, WA and Detroit, MI) with distinct sources and chemical composition of PM. Brain tissue was collected after the exposures were completed and analyzed for biomarkers of oxidative stress. The antioxidant glutathione (GSH) was reduced in the brains of mice exposed to CAPs in Michigan but not in Washington. In contrast the lipid peroxidation product 4-hydroxyalkenal (HNE) was significantly increased in the membrane fraction of brain tissue of mice exposed to CAPs in Washington but not in Michigan. No significant differences were observed in protein carbonyl levels, a biomarker of protein oxidation, although the levels were slightly higher in the cytoplasmic fraction of brain tissue from animals exposed to CAPs when compared to controls regardless of exposure site. The results suggest that PM from different sou...
Due to their phylogenetic proximity to human, non-human primates (NHP) are considered an adequate... more Due to their phylogenetic proximity to human, non-human primates (NHP) are considered an adequate choice for basic and pre-clinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of TLR4 suppressing the LPS-induced pro-inflammatory cytokine storm. The present study aimed to demonstrate that Fh15 suppress the cytokine storm and other inflammatory markers during the early phase of an endotoxemia induced in rhesus macaques by i.v. infusion with lethal doses of live E. coli. Fh15 was administrated as isotonic infusion 30 min prior to the bacterial infusion. Among the no...
BACKGROUND Status epilepticus (SE) is a prolonged and continuous seizure that lasts for at least ... more BACKGROUND Status epilepticus (SE) is a prolonged and continuous seizure that lasts for at least 5 minutes. An episode of SE in a healthy system can lead to the development of spontaneous seizures and cognitive deficits which may be accompanied by hippocampal injury and microgliosis. Although the direct mechanisms underlying the SE-induced pathophysiology remain unknown, a candidate mechanism is hyperactivation of the classical complement pathway (C1q-C3 signaling). We recently reported that SE triggers an increase in C1q-C3 signaling in the hippocampus that closely paralleled cognitive decline. Thus, we hypothesized that blocking activation of the classical complement pathway immediately after SE may prevent the development of SE-induced hippocampal-dependent learning and memory deficits. METHODS Because C1 esterase inhibitor (C1-INH) negatively regulates activation of the classical complement pathway, we used this drug to test our hypothesis. Two groups of male rats were subjected to 1 hr of SE with pilocarpine (280-300 mg/kg, i.p.), and treated with either C1-INH (SE+C1-INH, 20 U/kg, s.c.) or vehicle (SE+veh) at 4, 24, and 48 hours after SE. Control rats were treated with saline. Body weight was recorded up to 23 days after SE. At this time, recognition and spatial memory were determined using novel object recognition (NOR) and Barnes maze (BM), respectively, as well as locomotion and anxiety-like behaviors using open field (OF). Histological and biochemical methods were used to measure hippocampal injury including cell death, microgliosis, and inflammation. RESULTS One day after SE, both SE groups had a significant loss of body weight compared to controls (p<0.05). By day 14, the weight of SE+C1-INH rats was significantly higher than SE+veh rats (p<0.05), and was not different from controls (p>0.05). At 14 days post-SE, SE+C1-INH rats displayed higher mobility (distance travelled and average speed, p<0.05) and had reduced anxiety-like behaviors (outer duration, p<0.05) than control or SE+veh rats. In NOR, control rats spent significantly more time exploring the novel object vs. the familiar (p<0.05), while rats in both SE groups spent similar amount of time exploring both objects. During days 1-4 of BM training, the escape latency of the control group significantly decreased over time (p<0.05), whereas that of the SE groups did not improve (p>0.05). Compared to vehicle-treated SE rats, SE+C1-INH rats had increased levels of C3 and microglia in the hippocampus, but lower levels of caspase-3 and synaptic markers. CONCLUSIONS These findings suggest that acute treatment with C1-INH after SE may have some protective, albeit limited, effects on the physiological recovery of rats' weight and some anxiolytic effects, but does not attenuate SE-induced deficits in hippocampal-dependent learning and memory. Reduced levels of caspase-3 suggest that treatment with C1-INH may protect against cell death, perhaps by regulating inflammatory pathways and promoting phagocytic/clearance pathways.
Epidemiological studies have reported associations between exposure to ambient particulate matter... more Epidemiological studies have reported associations between exposure to ambient particulate matter (PM) and neurocognitive impairments. Children are particularly vulnerable to the effects of PM since their CNS is still in development, especially in regions related to executive functions (EFs). Toxicological studies have reported oxidative stress and neuroinflammatory responses in mice exposed to different types of PM. However, most studies have focused on prenatal, perinatal, and adult PM exposures. The goal of this study was to assess if PM exposure impairs the postnatal development of EF. We hypothesized that exposure to diesel exhaust particles (DEP) will impair EFs by inducing inflammatory responses in the CNS and lungs. To test this hypothesis, female and male C57BL/6J mice (n=14/group) were exposed intranasally to either saline or increasing doses of DEP during postnatal days (PND) 25 to 33. General cognitive abilities and executive function were evaluated on PND 36–38 with the Puzzle Box paradigm. Mice were euthanized on PND 39 and the tissue was collected to measure the concentration of proinflammatory cytokines in the CNS and assess inflammatory cell influx into the lungs. In the brain, the levels of IL-6 and GM-CSF, but not TNFα, significantly increased in a dose-dependent manner. In the lungs, a dose-dependent influx of inflammatory cells was also observed. The results showed that mice exposed to DEP had concomitant deficits in cognitive processes related to executive functions and inflammatory responses in the brain and lungs. This suggest that DEP induced pro-inflammatory responses might be associated with deficitis in the postnatal development of EFs. In the future, the role of microglia activation will be explored. Supported by Puerto Rico IDeA Network of Biomedical Research Excellence 5P20GM103475-18.
Cervical cancer (CC) is women’s fourth most common cancer worldwide. A worrying increase in CC ra... more Cervical cancer (CC) is women’s fourth most common cancer worldwide. A worrying increase in CC rates in Hispanics suggests that besides Human Papillomaviruses infections, there may be other biological causes promoting the disease. We hypothesized that the cervical microbiome and the epithelial microenvironment favoring inflammation is conducive to disease progression. There is a lack of studies examining the part played by microbial populations in the development of precancerous lesions into cancer in Hispanic women. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation in Hispanic women living in PR while considering cervical neoplasia and HPV infection. Cervical samples collected from 91 participants coming to clinics in San Juan, underwent 16S rRNA genes (V4 region) profiling, and cytokines were measured using Luminex MAGPIX technology. Cytokines were grouped as inflammatory (IL-1β, TNFα, IFNγ, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1...
Recent studies suggest that the cervical microbiome can strongly influence inflammation and pre-c... more Recent studies suggest that the cervical microbiome can strongly influence inflammation and pre-cancerous lesion progression. However, research focused on understanding the role of microbial communities in the progression of pre-cancerous lesions to cancer in Latino women is scarce. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation while considering cervical neoplasia and HPV infection in Puerto Rican women. We collected cervical swabs and lavages from 142 participants coming to colposcopy clinics in San Juan, Puerto Rico. Genomic DNA was extracted from swabs, and 16S rDNA V4 region genes were amplified and sequenced by Illumina MiSeq. Inflammatory (IL-1β, TNFa, IFNg, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1), and trafficking (IL-8, MIP1a, MCP1, IP10) cytokines were measured from cervical lavages, using Luminex MAGPIX technology. Cytokines were related to microbes via an inflammation scoring index based on the quartile and tercile di...
Parasitic helminths and helminth-derived molecules have demonstrated to possess powerful anti-inf... more Parasitic helminths and helminth-derived molecules have demonstrated to possess powerful anti-inflammatory properties and confirmed therapeutic effects on inflammatory diseases. The helminth Fasciola hepatica has been reported to suppress specific Th1 specific immune responses induced by concurrent bacterial infections, thus demonstrating its anti-inflammatory ability in vivo. In this study, we demonstrate that native F. hepatica glutathione S-transferase (nFhGST), a major parasite excretory-secretory antigen, majorly comprised of Mu-class GST isoforms, significantly suppresses the LPS-induced TNFα and IL1β of mouse bone-marrow derived macrophages in vitro and the pro-inflammatory cytokine/chemokine storm within C57BL/6 mice exposed to lethal doses of LPS increasing their survival rate by more than 85%. Using THP1-Blue CD14 cells, a human monocyte cell line, we also demonstrate that nFhGST suppresses NF-κB activation in response to multiple TLR-ligands, including whole bacteria clin...
Exposure to airborne particulate matter (PM) has been associated with the transcriptional up-regu... more Exposure to airborne particulate matter (PM) has been associated with the transcriptional up-regulation of pro-inflammatory mediators. However, the effect of PM on post-transcriptional regulation of pro-inflammatory mediators has not been fully explored. In this study, we examined the acute effect of organic extracts from urban PM, rural PM and diesel exhaust particles (DEP) on the post-transcriptional control of interleukin-6 (IL-6) and interleukin-8 (CXCL8) using a human bronchial epithelial cell line. Both PM and DEP extracts induced the release of IL-6 and CXCL8 after 24 h of exposure. Time-course experiments were conducted to examine changes in mRNA steady-state levels and half-lives. The steady-state levels of CXCL8 mRNA increase at 15 min on cells exposed to both PM and DEP extracts. Meanwhile only the urban extract induced significant increases of IL-6 mRNA levels at 15 min. Indirect measurements of IL-6 mRNA half-life showed a dramatic increase in cells exposed to the organ...
Epidemiological studies have reported associations between exposure to ambient particulate matter... more Epidemiological studies have reported associations between exposure to ambient particulate matter (PM) and neurocognitive impairments. Children are particularly vulnerable to the effects of PM since their CNS is still in development, especially in regions related to executive functions (EFs). Toxicological studies have reported oxidative stress and neuroinflammatory responses in mice exposed to different types of PM. However, most studies have focused on prenatal, perinatal, and adult PM exposures. The goal of this study was to assess if PM exposure impairs the postnatal development of EF. We hypothesized that exposure to diesel exhaust particles (DEP) will impair EFs by inducing inflammatory responses in the CNS and lungs. To test this hypothesis, female and male C57BL/6J mice (n=14/group) were exposed intranasally to either saline or increasing doses of DEP during postnatal days (PND) 25 to 33. General cognitive abilities and executive function were evaluated on PND 36–38 with the...
Dengue (DENV) and Zika (ZIKV) are flaviviruses that co-circulate throughout the tropical and subt... more Dengue (DENV) and Zika (ZIKV) are flaviviruses that co-circulate throughout the tropical and subtropical regions. The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection. We show that CD4+ depletion in DENV-primed animals followed by ZIKV-DENV resulted in delayed viremia followed by increased viral replication in tertiary infections and dysregulated adaptive immune responses compared to ZIKV-primed animals followed by DENV-DENV infections. We show a delay in DENV-specific IgM/IgG antibody titers and neutralization in the DENV-primed CD4-depleted animals but not in ZIKV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in viremia control and priming of early and robust neutralizing antibody respon...
Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States ... more Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects have been attributed to the persistent inflammatory cascade.
The determination of the dose of inhaled aerosol particles in animal subjects is not a trivial ex... more The determination of the dose of inhaled aerosol particles in animal subjects is not a trivial exercise. In its simplest form, the dose is the amount (particle number, mass, or other relevant metric) that deposits in the respiratory tract. The amount deposited will depend on the aerosol particle sizes (e.g. the aerodynamic diameter size distribution), the duration of exposure, the exposure system's delivery efficiency, the subject's ventilation rate, the species and strain, and other factors. Similarly, species differences in the clearance rates of deposited particles will influence the time integrated particle doses. In practice, particle doses are estimated using mathematical models, previous experimental dosimetry data, tracers of the inhaled particles, and biomarkers of exposure. With care, desired aerosol doses can be achieved and documented.
Conclusions CAPs or particle-free air for 5 hours a day, 5 days per week, for a period of 6 month... more Conclusions CAPs or particle-free air for 5 hours a day, 5 days per week, for a period of 6 months. The whole-body inhalation exposures were conducted in two urban cities (Seattle, WA and Detroit, MI) with distinct sources and chemical composition of PM. Brain tissue was collected after the exposures were completed and analyzed for biomarkers of oxidative stress. The antioxidant glutathione (GSH) was reduced in the brains of mice exposed to CAPs in Michigan but not in Washington. In contrast the lipid peroxidation product 4-hydroxyalkenal (HNE) was significantly increased in the membrane fraction of brain tissue of mice exposed to CAPs in Washington but not in Michigan. No significant differences were observed in protein carbonyl levels, a biomarker of protein oxidation, although the levels were slightly higher in the cytoplasmic fraction of brain tissue from animals exposed to CAPs when compared to controls regardless of exposure site. The results suggest that PM from different sou...
Due to their phylogenetic proximity to human, non-human primates (NHP) are considered an adequate... more Due to their phylogenetic proximity to human, non-human primates (NHP) are considered an adequate choice for basic and pre-clinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of TLR4 suppressing the LPS-induced pro-inflammatory cytokine storm. The present study aimed to demonstrate that Fh15 suppress the cytokine storm and other inflammatory markers during the early phase of an endotoxemia induced in rhesus macaques by i.v. infusion with lethal doses of live E. coli. Fh15 was administrated as isotonic infusion 30 min prior to the bacterial infusion. Among the no...
BACKGROUND Status epilepticus (SE) is a prolonged and continuous seizure that lasts for at least ... more BACKGROUND Status epilepticus (SE) is a prolonged and continuous seizure that lasts for at least 5 minutes. An episode of SE in a healthy system can lead to the development of spontaneous seizures and cognitive deficits which may be accompanied by hippocampal injury and microgliosis. Although the direct mechanisms underlying the SE-induced pathophysiology remain unknown, a candidate mechanism is hyperactivation of the classical complement pathway (C1q-C3 signaling). We recently reported that SE triggers an increase in C1q-C3 signaling in the hippocampus that closely paralleled cognitive decline. Thus, we hypothesized that blocking activation of the classical complement pathway immediately after SE may prevent the development of SE-induced hippocampal-dependent learning and memory deficits. METHODS Because C1 esterase inhibitor (C1-INH) negatively regulates activation of the classical complement pathway, we used this drug to test our hypothesis. Two groups of male rats were subjected to 1 hr of SE with pilocarpine (280-300 mg/kg, i.p.), and treated with either C1-INH (SE+C1-INH, 20 U/kg, s.c.) or vehicle (SE+veh) at 4, 24, and 48 hours after SE. Control rats were treated with saline. Body weight was recorded up to 23 days after SE. At this time, recognition and spatial memory were determined using novel object recognition (NOR) and Barnes maze (BM), respectively, as well as locomotion and anxiety-like behaviors using open field (OF). Histological and biochemical methods were used to measure hippocampal injury including cell death, microgliosis, and inflammation. RESULTS One day after SE, both SE groups had a significant loss of body weight compared to controls (p<0.05). By day 14, the weight of SE+C1-INH rats was significantly higher than SE+veh rats (p<0.05), and was not different from controls (p>0.05). At 14 days post-SE, SE+C1-INH rats displayed higher mobility (distance travelled and average speed, p<0.05) and had reduced anxiety-like behaviors (outer duration, p<0.05) than control or SE+veh rats. In NOR, control rats spent significantly more time exploring the novel object vs. the familiar (p<0.05), while rats in both SE groups spent similar amount of time exploring both objects. During days 1-4 of BM training, the escape latency of the control group significantly decreased over time (p<0.05), whereas that of the SE groups did not improve (p>0.05). Compared to vehicle-treated SE rats, SE+C1-INH rats had increased levels of C3 and microglia in the hippocampus, but lower levels of caspase-3 and synaptic markers. CONCLUSIONS These findings suggest that acute treatment with C1-INH after SE may have some protective, albeit limited, effects on the physiological recovery of rats' weight and some anxiolytic effects, but does not attenuate SE-induced deficits in hippocampal-dependent learning and memory. Reduced levels of caspase-3 suggest that treatment with C1-INH may protect against cell death, perhaps by regulating inflammatory pathways and promoting phagocytic/clearance pathways.
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