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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    307—Brain Injury: Cellular and Molecular Mechanisms

    Monday, November 11, 2013, 8:00 am - 11:30 am

    307.09: Cox-2 regulation differs between sexes in the secondary inflammatory response following experimental penetrating brain injury in rats

    Location: 32B

    ">*M. G‹NTHER1, S. PLANTMAN1, J. DAVIDSSON2, M. ANG…RIA1, T. MATHIESEN1, M. RISLING1;
    1Karolinska Institutet, Stockholm, Sweden; 2Chalmers Univ. of Technol., Gothenburg, Sweden

    Abstract Body: Introduction Traumatic brain injury is followed by a secondary inflammatory response. Females are better protected from adverse effects of this process in animal models and human epidemiological studies. The reason for this is not fully known. We examined the inflammatory response following experimental TBI in male and female rats. Methods Parietal contusions using a penetrating brain injury model were produced in male and female rats (n=5). After 24 h and 72 h the brains were removed, cut in 14 µm coronal and transversal sections and subjected to immunohistochemical analyses for protein expression and in situ hybridization for mRNA detection. We analyzed the expression of the proinflammatory enzymes Cox-2 and iNOS, markers of astrogliosis (GFAP), microgliosis (Osteopontin), peroxynitrite levels by surrogate measure 3-Nitrotyrosine, and neuronal degeneration (Fluoro Jade). Results GFAP mRNA was upregulated in the region of interest (ROI); the perilesional area at 24 h and 72 h. No difference was seen between sexes. Osteopontin was upregulated in the ROI at 24 h. No difference was seen between sexes. Cox-2 mRNA was elevated in the cortical areas of the ROI with a significant upregulation
    in male rats at 24 and 72 h (p<0.05). iNOS mRNA levels and protein expression was upregulated in the ROI at 24 h. No difference was seen between sexes. 3-Nitrotyrosine was upregulated in the ROI after 24 h. No difference was seen between sexes. Fluoro Jade stained neuronal degeneration was upregulated in the ROI at 24 h. No difference was seen between sexes. Conclusions We found that the Cox-2 mediated inflammatory response differed between female and male rats following TBI. Cox-2 is partly expressed under physiological conditions in the brain but mainly induced by proinflammatory mediators. It is suspected to be involved in various neurodegenerative diseases, and the regulation of Cox-2 and iNOS has been shown to be interconnected. The nitric oxide producing enzyme iNOS is induced following trauma, leading to oxidative stress through the creation of peroxynitrite. iNOS and peroxynitrite expression did not differ between sexes. Astrogliosis and microgliosis were found in the perilesional area with a similar expression between sexes. Our findings from this pilot study indicate that the sex specific trait of the secondary inflammatory response may be connected to prostaglandin regulation. The difference did not lead to altered neuronal death at 24 h. This heterogeneity may in part explain sex dependent variances in outcome after TBI.

    Lay Language Summary: Important enzyme may
    influence better healing in females after traumatic brain injury

    It is previously known that females are better protected from
    adverse effects and show better outcome after traumatic brain injury (TBI). We here
    present results in rats showing that the regulation of the enzyme Cox-2 in the
    brain after TBI is sex dependent. Cox-2 is one of the key enzymes in the
    inflammatory response of the body. This difference in regulation may in part
    explain why females heal better and may have implications on how to treat TBI
    as well as future drug development efforts.
    Traumatic
    brain injury is a leading cause of death and disability among young adults in
    the industrialized world. It is caused by traumatic events to the head such as
    car accidents and football games. The primary
    impact leads to the immediate loss of brain tissue and is followed by a
    secondary inflammation causing further damage to the brain. Despite intense
    research efforts no substance has so far been deemed effective in treating the
    secondary inflammation in human trials.
    The novel finding of the sex dependent difference in Cox-2
    regulation may in part explain why females are better protected from the secondary
    inflammation after TBI in experimental and human epidemiological studies. Beneficial
    effects of anti-inflammatory drugs after TBI have also mainly been seen in males.
    The protective mechanisms have been related to the female sex hormones estrogen
    and progesterone, but the exact mechanisms for protection have not been
    clarified.
    The Cox-2 enzyme is responsible for the regulation of a major
    group of molecules that act as important mediators in inflammation, called
    prostaglandins. They exhibit a variety of physiological
    effects such as blood vessel contraction, cell growth and programmed cell death. Cox-2 is up-regulated in inflammation and may
    be inhibited by the widely used anti-inflammatory drugs NSAID and acetylic salicylic
    acid, lowering inflammation and pain in the body. So far, these positive
    effects of inhibition of Cox-2 have not been found in the brain after TBI.
    Male and female rats (n=5) were
    anesthetized and subjected to TBI. After 24 and 72 hours, proteins and enzymes
    were detected and analyzed in the brains.
    We found that the activation of
    supporting and inflammatory cells was similar between the groups, confirming a
    comparable level of trauma. Cox-2 was up-regulated in males compared to females
    at both time points. Enzymes and markers involved in oxidative stress, a common
    complication of inflammation, did not differ. Further, we measured the survival
    of neuronal cells, not detecting any difference. We concluded that the sex
    dependent differences of the inflammation may be due to prostaglandin
    regulation rather than oxidative stress, and that no apparent difference in
    cell survival was seen at this early stage.
    Our future research will focus on
    the sex-dependent regulatory mechanisms of Cox-2 and prostaglandins after TBI.
    We will seek to further elucidate the mechanisms behind the better protection
    of females, which may be used in future treatment of TBI as well as
    individualized treatment of the secondary inflammation.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    307—Brain Injury: Cellular and Molecular Mechanisms

    Monday, November 11, 2013, 8:00 am - 11:30 am

    307.09: Cox-2 regulation differs between sexes in the secondary inflammatory response following experimental penetrating brain injury in rats

    Location: 32B

    ">*M. G‹NTHER1, S. PLANTMAN1, J. DAVIDSSON2, M. ANG…RIA1, T. MATHIESEN1, M. RISLING1;
    1Karolinska Institutet, Stockholm, Sweden; 2Chalmers Univ. of Technol., Gothenburg, Sweden

    Abstract Body: Introduction Traumatic brain injury is followed by a secondary inflammatory response. Females are better protected from adverse effects of this process in animal models and human epidemiological studies. The reason for this is not fully known. We examined the inflammatory response following experimental TBI in male and female rats. Methods Parietal contusions using a penetrating brain injury model were produced in male and female rats (n=5). After 24 h and 72 h the brains were removed, cut in 14 µm coronal and transversal sections and subjected to immunohistochemical analyses for protein expression and in situ hybridization for mRNA detection. We analyzed the expression of the proinflammatory enzymes Cox-2 and iNOS, markers of astrogliosis (GFAP), microgliosis (Osteopontin), peroxynitrite levels by surrogate measure 3-Nitrotyrosine, and neuronal degeneration (Fluoro Jade). Results GFAP mRNA was upregulated in the region of interest (ROI); the perilesional area at 24 h and 72 h. No difference was seen between sexes. Osteopontin was upregulated in the ROI at 24 h. No difference was seen between sexes. Cox-2 mRNA was elevated in the cortical areas of the ROI with a significant upregulation
    in male rats at 24 and 72 h (p<0.05). iNOS mRNA levels and protein expression was upregulated in the ROI at 24 h. No difference was seen between sexes. 3-Nitrotyrosine was upregulated in the ROI after 24 h. No difference was seen between sexes. Fluoro Jade stained neuronal degeneration was upregulated in the ROI at 24 h. No difference was seen between sexes. Conclusions We found that the Cox-2 mediated inflammatory response differed between female and male rats following TBI. Cox-2 is partly expressed under physiological conditions in the brain but mainly induced by proinflammatory mediators. It is suspected to be involved in various neurodegenerative diseases, and the regulation of Cox-2 and iNOS has been shown to be interconnected. The nitric oxide producing enzyme iNOS is induced following trauma, leading to oxidative stress through the creation of peroxynitrite. iNOS and peroxynitrite expression did not differ between sexes. Astrogliosis and microgliosis were found in the perilesional area with a similar expression between sexes. Our findings from this pilot study indicate that the sex specific trait of the secondary inflammatory response may be connected to prostaglandin regulation. The difference did not lead to altered neuronal death at 24 h. This heterogeneity may in part explain sex dependent variances in outcome after TBI.

    Lay Language Summary: Important enzyme may
    influence better healing in females after traumatic brain injury

    It is previously known that females are better protected from
    adverse effects and show better outcome after traumatic brain injury (TBI). We here
    present results in rats showing that the regulation of the enzyme Cox-2 in the
    brain after TBI is sex dependent. Cox-2 is one of the key enzymes in the
    inflammatory response of the body. This difference in regulation may in part
    explain why females heal better and may have implications on how to treat TBI
    as well as future drug development efforts.
    Traumatic
    brain injury is a leading cause of death and disability among young adults in
    the industrialized world. It is caused by traumatic events to the head such as
    car accidents and football games. The primary
    impact leads to the immediate loss of brain tissue and is followed by a
    secondary inflammation causing further damage to the brain. Despite intense
    research efforts no substance has so far been deemed effective in treating the
    secondary inflammation in human trials.
    The novel finding of the sex dependent difference in Cox-2
    regulation may in part explain why females are better protected from the secondary
    inflammation after TBI in experimental and human epidemiological studies. Beneficial
    effects of anti-inflammatory drugs after TBI have also mainly been seen in males.
    The protective mechanisms have been related to the female sex hormones estrogen
    and progesterone, but the exact mechanisms for protection have not been
    clarified.
    The Cox-2 enzyme is responsible for the regulation of a major
    group of molecules that act as important mediators in inflammation, called
    prostaglandins. They exhibit a variety of physiological
    effects such as blood vessel contraction, cell growth and programmed cell death. Cox-2 is up-regulated in inflammation and may
    be inhibited by the widely used anti-inflammatory drugs NSAID and acetylic salicylic
    acid, lowering inflammation and pain in the body. So far, these positive
    effects of inhibition of Cox-2 have not been found in the brain after TBI.
    Male and female rats (n=5) were
    anesthetized and subjected to TBI. After 24 and 72 hours, proteins and enzymes
    were detected and analyzed in the brains.
    We found that the activation of
    supporting and inflammatory cells was similar between the groups, confirming a
    comparable level of trauma. Cox-2 was up-regulated in males compared to females
    at both time points. Enzymes and markers involved in oxidative stress, a common
    complication of inflammation, did not differ. Further, we measured the survival
    of neuronal cells, not detecting any difference. We concluded that the sex
    dependent differences of the inflammation may be due to prostaglandin
    regulation rather than oxidative stress, and that no apparent difference in
    cell survival was seen at this early stage.
    Our future research will focus on
    the sex-dependent regulatory mechanisms of Cox-2 and prostaglandins after TBI.
    We will seek to further elucidate the mechanisms behind the better protection
    of females, which may be used in future treatment of TBI as well as
    individualized treatment of the secondary inflammation.