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

    836—Steroids in Cognition, Arousal, and Associated Endpoints

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    836.11: Nutrition, gender, and brain plasticity: DHA preconditions the action of progesterone on brain trauma

    Location: Halls B-H

    ">*E. TYAGI1, F. GOMEZ-PINILLA1,2;
    1Integrative Biol. and Physiol., Univ. of California Los Angeles (UCLA), Los Angeles, CA; 2Dept. of Neurosurg., UCLA brain injury research center, Los Angeles, CA

    Abstract Body: The outcome of traumatic brain injury (TBI) is clearly influenced by gender, but the mechanisms and vulnerability factors involved are poorly understood. It is becoming increasingly evident that the functions of gonadal steroids, such as progesterone, extend well beyond reproduction, and can affect the outcome of TBI (indeed progesterone in in phase III clinical trials). In turn, diets, and particularly maternal nutrition, are likely determinants of brain plasticity. The present study was planned to analyze the possibility that the therapeutic action of progesterone on traumatic brain injury (TBI) could depend on dietary habits. We have evaluated how the action of DHA interacts with Progesterone treatment incurred in adult life after TBI. Pregnant Sprague Dawley rats and their female offspring were kept on n-3 adequate or deficient diet for 15 weeks. Ovariectomy was performed after 12 weeks of weaning, and the animals were subjected to either sham or fluid percussion injury (FPI). Exposure to dietary n-3 fatty acid deficiency aggravated the effects of TBI on anxiety-like behavior while n-3 preconditioning helped the animals to resist the effects of TBI. A similar pattern was observed for markers of membrane homeostasis such as 4HNE and sPLA2, synaptic plasticity such as BDNF, syntaxin-3 and GAP43, and for growth inhibitory molecules such as myelin-associated glycoprotein (MAG) and Nogo-A. Anxiety like behavior varied relative to levels of STX-3 and Nogo-A, suggesting that this behavior recruits synaptic and axonal systems. These results reveal the importance of omega-3 preconditioning during early life and progesterone treatment for brain plasticity and axonal growth in adulthood. Results suggest that the action of progesterone is particularly relevant for TBI during n-3 deficient condition. This study suggests that the DHA diet and progesterone may help to maintain synaptic functions and membrane stability. The overall evidence indicates that DHA diet and progesterone is a powerful strategy that can be applied to alleviate neurological disorders. In particular, our results are significant to understand the influence of pre-injury conditions such as dietary factors on the capacity of patients for healing following neurological damage. These results have important implications for the clinical management of TBI in the population consuming subnormal content of DHA during brain development.

    Lay Language Summary: Traumatic brain injury (TBI) is a leading cause of death and disability globally, and a major public health issue. The Centers for Disease Control and Prevention (CDC) estimates that 2% of the U.S. population lives with the effects of a TBI, of which about one third are women. The health-related consequences of TBI have been almost exclusively studied in a male, which intuitively is far from the women reality, as to females hormones likely influence healing.
    It has become increasingly evident that the functions of gonadal steroid hormones, such as estrogen and progesterone, extend well beyond reproduction. Pre-clinical and clinical data accumulating over the last several years indicate that progesterone may be highly effective in the treatment of TBI. Progesterone has been shown to improve behavioral and functional recovery and to reduce inflammation, oxidative damage, cerebral edema, and neuronal cell death after TBI. Multiple regions within the central nervous system (CNS) are targeted by progesterone, including areas crucial for processing of higher order function such as the hippocampus and cortex.
    Although the outcome of TBI is clearly influenced by gender, the factors involved are poorly understood. Diet is a vital aspect of daily living, which seems to have the extraordinary power to alter the course of diseases and treatments. In particular, the omega-3 fatty acid DHA has been shown to protect the brain against the effects of TBI; however, there is not a clear dimension how the action of DHA may be affected by the hormonal state. The fact that progesterone concentration fluctuates in females across the menstrual cycle, and its efficacy for the treatment of TBI may also be affected by the dietary pattern of females. Accordingly, we focused the current studies in female rodents to evaluate whether DHA in the diet influences the efficacy of progesterone for the treatment of TBI.
    Low consumption of DHA in humans has been associated with increased risk of suicide in a population with high risk of trauma. Recent reports show that DHA is significantly reduced in the postmortem prefrontal cortex of female, but not male, patients with major depression. These findings suggest that the action of DHA in psychiatric disorders may depend on the hormonal status of females. Indeed, it is known that the incidence of major psychiatric illnesses in women increases during periods of ovarian hormonal fluctuations such as the postmenopausal period. The implication of this research is further significant based on the information that diet is the only source of DHA for the brain, although consumption of DHA is below recommended levels in the western society.
    We found that deficiency in dietary n-3 fatty acid aggravated the effects of TBI, whereas progesterone replacement counteracted the effects of TBI on the animals reared under n-3 deficiency. These effects were expressed in several molecular systems important for neuronal healing and the behavior of the animals. Our results are significant to understand how omega-3 fatty acids during brain development can affect the capacity of the brain to resist disorders in adult life. The overall evidence indicates that the female brain poses particular challenges for the planning of pharmacological strategies to treat neurological disorders.