Neuroscience
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The aging process is known to coincide with a decline in circulating sex hormone levels in both men and women. Due to an increase in the average lifespan, a growing number of post-menopausal women are now receiving hormone therapy for extended periods of time. Recent findings of the Women's Health Initiative, however, have called into question the benefits of long-term hormone therapy for treating symptoms of menopause. ⋯ This review focuses on emerging information that estradiol can also activate a repertoire of membrane-initiated signaling pathways and that these rapid signaling events lead to functional changes at the cellular level. The various types of cells in the brain can respond differently to estradiol treatment based on the signaling properties of the cell, as well as which receptor, estrogen receptor alpha and/or estrogen receptor beta, is expressed. Taken together, these findings suggest that the estradiol-induced activation of membrane-initiated signaling pathways occurs in a cell-type specific manner and can differentially influence how the cells respond to various insults.
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Estrogen has the potential to influence brain processes implicated in Alzheimer's disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer's disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women's Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. ⋯ Finally, Women's Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women's Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer's disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.
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The nervous system synthesizes steroids that regulate the development and function of neurons and glia, and have neuroprotective properties. The first step in steroidogenesis involves the delivery of free cholesterol to the inner mitochondrial membrane where it can be converted into pregnenolone by the enzyme cytochrome P450side chain cleavage. The peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein are involved in this process and appear to function in a coordinated manner. ⋯ The steroidogenic acute regulatory protein gene may be under the control of diverse mechanisms in different neural cell types, since its expression is upregulated by cyclic AMP (cAMP) in gliomas and astrocytes in culture and downregulated by cyclic AMP (cAMP) in Schwann cells. In addition, activation of N-methyl-D-aspartate receptors, and the consequent rise in intracellular calcium levels, activates steroidogenic acute regulatory protein and steroidogenesis in hippocampal neurons. In conclusion, steroidogenic acute regulatory protein is regulated in the nervous system by different physiological and pathological conditions and may play an important role during brain development, aging and after injury.
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Glutamate is a primary excitatory neurotransmitter in the mammalian CNS. Glutamate released from presynaptic neurons is cleared from the synaptic cleft passively by diffusion and actively by glutamate transporters. In this study, the role of glutamate transporters in sensory processing in the spinal cord has been investigated in behavioral, in vivo and in vitro experiments. ⋯ Whole cell recordings made from superficial dorsal horn neurons in an isolated whole spinal cord from newborn rats (2-3 weeks old) revealed that bath-applied L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM) produced partial membrane depolarization, increased spontaneous action potentials with decreased neuronal membrane resistance and time constant, but without significant changes of capacitance. Finally, the amplitude and duration of primary afferent evoked-excitatory postsynaptic currents recorded from neurons in the substantia gelatinosa in the spinal slices from young adult rats (6-8 weeks old) were increased in the presence of L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM). This study indicates that glutamate transporters regulate baseline excitability and responses of dorsal horn neurons to peripheral stimulation, and suggests that dysfunction of glutamate transporters may contribute to certain types of pathological pain.
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It is now clear that the study of the effects exerted by steroids on the nervous system may be considered as one of the most interesting and promising topics for biomedical research. Indeed, new effects, mechanisms of action and targets are becoming more and more evident suggesting that steroids are not only important key regulators of nervous system function but they may also represent a new therapeutic tool to combat certain diseases of the nervous system. The present review summarizes recent observations on this topic indicating that while the concept of the nervous system as a target for steroid hormones has been appreciated for decades, a promising new era for the study of these molecules and their actions in the nervous system has been initiated in the last few years.