Differential effects of estrogen in the injured forebrain of young adult and reproductive senescent animals
Introduction
The gonadal hormone estrogen affects several neural groups, including the forebrain cholinergic system, and regulates the expression of key enzymes, cytoskeletal proteins and growth factors. Many of these events are critical during neural development [27], [45], [53], [72], [79], [80], and several of them continue to occur in the adult brain as well. Besides its actions on forebrain growth factor expression [68], [69], [70] and the basal forebrain cholinergic system [21], [42], [44], [54], [67], [71], estrogen also attenuates tissue damage resulting from experimental injury models such as cerebral ischemia [16], [64], septo-hippocampal transection [57] and excitotoxic lesions [71]. Collectively, this evidence supports the hypothesis that estrogen replacement may be neuroprotective in forebrain degenerative disease.
Age-related changes in hormone responsiveness, however, may decrease estrogens ability to attenuate tissue damage in the forebrain. Estrogen-mediated LH surges are blunted in middle-aged rats [87] and aging affects the density of alpha-1 adrenergic receptors and their diurnal rhythms in specific hypothalamic nuclei [85]. In some cases specific genes such as GAP-43 mRNA [66], neurotensin mRNA [20] and ChAT mRNA [65] remain sensitive to estrogen in both young and aging animals, while in other cases such as trkA, the NGF specific tyrosine kinase receptor, the gene is equally sensitive to estrogen in the young and old animals in the nucleus basalis region but not in the horizontal limb [65]. Using a model of hormonal aging, i.e. reproductive senescence, our recent data shows that estrogen has paradoxical effects on the young adult and reproductive senescent female rat that can be classified into two patterns. Genes were either refractory to estrogen treatment, as in the case of trkA and trkB which estrogen typically increases in the olfactory bulb of young adults, or responded to estrogen in a manner diametrically opposite to that of young adults, as in the case of BDNF and p75 [35]. The present study therefore investigated whether estrogen would be neuroprotective to the aging brain as has been shown for the young adult animal.
The olfactory bulb-hlDBB circuit, where age-related regulation of neurotrophins were observed, is prototypical of other estrogen-sensitive forebrain cholinergic pathways radiating from the basal forebrain to targets such as the hippocampus and cortex. Efferent neurons in these circuits synthesize neurotrophins that are retrogradely transported to their basal forebrain afferents and neurons in these circuits are vulnerable to Alzheimer’s disease (AD)-related lesions. In view of emerging evidence that inflammation may be a critical component of neurodegenerative disease, the present studies investigated whether estrogen replacement would alter the inflammatory phenotype resulting from excitotoxic lesions of the olfactory bulb, and whether this regulation would differ in young adult and reproductive senescent animals. To assess the inflammatory response following excitotoxic lesions, we measured expression of IL-1β, a key pro-inflammatory cytokine, as well as IL-10, a cytokine typically produced by the Th2 class of helper T cells, which inhibit systemic inflammatory reactions. Our data reveal that estrogen replacement decreases the proinflammatory phenotype, derived as a ratio of IL-1β to IL-10, at the primary lesion site in young adult animals while exacerbating it in older animals. Furthermore, bulb lesions alter cytokine expression in the hlDBB afferent in old but not young animals, indicating that age may accelerate transneuronal toxicity in forebrain circuits.
Section snippets
Animals
All rats were purchased from Harlan Laboratories (IN) as young adults (∼250 g, 4 months; n=58). Reproductive senescent animals (13–16 months; 325–410 g) were used after they were retired from a breeding program (Alcohol and Brain Research Laboratory, J.R. West TAMUSHSC). These animals were used solely for breeding purposes. Retired breeders used in this study met previously established criteria [35] for reproductive senescence, which included 4–5 successful prior pregnancies followed by two
Confirmation of estrogen treatment
Ovariectomized animals replaced with an estrogen-containing pellet (E2) had an average plasma estradiol level of 57.64±6.19 pg/ml in young adult and 81.6±12.76 for the reproductive senescent animals, typical of hormonal levels seen at proestrus. The average weight gain as a result of estrogen treatment was −10.5 g (+5.68) in the reproductive senescent group and −0.75 g (+3.82) in the young adult group. In contrast, ovariectomized, placebo-replaced animals (OVX) had low estradiol levels in both
Discussion
Infectious or traumatic injury to the brain results in microglial activation, and the consequent release of inflammatory cytokines, such as the interleukins, initiates leukocyte recruitment. Inflammation, which is a primary component of the immune response, has both degenerative and reparative aspects. Prolonged neural inflammation, however, can lead to “bystander damage” of healthy neurons. Recent evidence indicates that inflammation may contribute to the etiology of Alzheimer’s disease (for
Acknowledgements
Supported by NS 39367. We thank Trichelle Newman and Debbie Geevarghese for technical assistance.
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Contributed equally to this work.