Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Jun 2010
Timing versus duration: determinants of anesthesia-induced developmental apoptosis in the young mammalian brain.
Rapidly accumulating evidence indicates that clinically used general anesthesia causes massive, widespread neuroapoptotic degeneration in the developing mammalian brain. Susceptibility to anesthesia-induced neurotoxicity has been documented in rats, mice, guinea pigs, primates, and in this study, piglets; in short, anesthesia-induced developmental neuroapoptosis is not species-dependent. ⋯ However, the highly reproducible findings in different species also indicate that the timing of exposure to anesthesia is critically important; that is, brain regions that are at the peak of synaptogenesis are most vulnerable even when the exposure to anesthesia is relatively brief. Because the peak of synaptogenesis is characterized by intense, highly programmed neuronal communication that is vital for the survival and proper function of immature neurons, we conclude that anesthesia causes severe disturbances in the fine equilibrium between excitatory and inhibitory neurotransmission in the developing mammalian brain, ultimately leading to neuronal redundancy and death.
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Ann. N. Y. Acad. Sci. · Jun 2010
Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury.
Neuropathic pain is a common problem following spinal cord injury (SCI). Effective analgesic therapy has been hampered by the lack of knowledge about the mechanisms underlying post-SCI neuropathic pain. Current evidence suggests GABAergic spinal nociceptive processing is a critical functional node in this complex phenotype, representing a potential target for therapeutic intervention. ⋯ Inhibition of NKCC1 with its potent antagonist bumetanide reduces pain behavior in rats following SCI. Moreover, the injured spinal cord tissues exhibit a significant transient upregulation of NKCC1 protein and a concurrent downregulation of KCC2 protein. Thus, imbalanced function of NKCC1 and KCC2 may contribute to the induction and maintenance of the chronic neuropathic pain following SCI.
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Ann. N. Y. Acad. Sci. · Jun 2010
Presynaptic inhibition of primary afferents by depolarization: observations supporting nontraditional mechanisms.
Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli and is controlled by pre- and postsynaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is probably the more powerful form of inhibitory control in all primary afferent fibers. A major mechanism producing afferent PSI is via a channel-mediated depolarization of their intraspinal terminals, which can be recorded extracellularly as a dorsal root potential (DRP). ⋯ There is still no "squeaky clean" evidence of this organization. This paper describes recent and historical work that supports the existence of PAD occurring by more direct pathways and with a complex pharmacology that questions the proprietary role of GABA and GABA(A) receptors in this process. Cholinergic transmission in particular may contribute significantly to PAD, including via direct release from primary afferents.
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Ann. N. Y. Acad. Sci. · Apr 2010
ReviewPsoriatic arthritis: clinical improvement and correlation with hormone axes in etanercept-treated patients.
In a chronic inflammatory disease, such as rheumatoid arthritis (RA), the hypothalamic-pituitary-adrenal axis is altered in three ways: (1) the inflammation-related spontaneous and stimulated secretion of cortisol is inadequate; (2) the inflammation-related secretion of adrenocorticotropic hormone (ACTH) is low; and (3) the levels of adrenal androgens decrease. In patients with RA, long-term therapy with anti-TNF therapy sensitizes the pituitary gland and improves adrenal androgen secretion. We have recently found that the mean serum levels of ACTH, cortisol, 17-hydroxyprogesterone (17OHP), and androstenedione (ASD) in 11 prednisolone-naïve patients with psoriatic arthritis did not markedly change during 12 weeks of etanercept treatment, nor did the serum cortisol/ACTH ratio. However, the greater increase in serum cortisol in comparison with serum 17OHP or ASD was related to clinical improvement, which indicates that the improvement was more related to the higher cortisol levels.
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Ann. N. Y. Acad. Sci. · Apr 2010
ReviewProthymosin alpha as robustness molecule against ischemic stress to brain and retina.
Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions, including memory, sensory perception, and motor skills. As necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. We identified the nuclear protein, prothymosin alpha (ProTalpha) from the conditioned medium of serum-free culture of cortical neurons as a key protein-inhibiting necrosis. ⋯ In the ischemic brain or retina, ProTalpha showed a potent inhibition of both necrosis and apoptosis. By use of anti-brain-derived neurotrophic factor or anti-erythropoietin IgG, we found that ProTalpha inhibits necrosis, but causes apoptosis, which is in turn inhibited by ProTalpha-induced neurotrophins under the condition of ischemia. From the experiment using anti-ProTalpha IgG or antisense oligonucleotide for ProTalpha, it was revealed that ProTalpha has a pathophysiological role in protecting neurons in stroke.