Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions.

BACKGROUND: Developmental neurotoxicity of ketamine, an N-methyl-D-aspartate receptor antagonist, must be considered due to its widespread uses for sedation/analgesia/anesthesia in pediatric and obstetric settings. Dose-dependent effects of ketamine on cellular proliferation in the neurogenic regions of rat fetal cortex [ventricular zone (VZ) and subventricular zone (SVZ)] were investigated in this in vivo study. METHODS: Timed-pregnant Sprague-Dawley rats at embryonic day 17 (E17) were given with different doses of ketamine intraperitoneally (0, 1, 2, 10, 20, 40, and 100 mg/kg). Proliferating cells in the rat fetal brains were labeled by injecting 100 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) intraperitoneally. BrdU-labeled cells were detected by immunostaining methods. The numbers of BrdU-positive cells in VZ and SVZ of rat fetal cortex were employed to quantify proliferation in the developing rat cortex. RESULTS: Ketamine dose-dependently reduced the number of BrdU-positive cells in VZ (P < 0.001) and SVZ (P < 0.001) of the rat fetal cortex. SVZ showed greater susceptibility to ketamine-induced reduction of proliferation in rat fetal cortex, occurring even at clinically relevant doses (2 mg/kg). CONCLUSION: These data suggest that exposure to ketamine during embryogenesis can dose-dependently inhibit the cellular proliferation in neurogenic regions of the rat fetal cortex.

In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis.

Interleukin-1 (IL-1), an inflammatory cytokine overexpressed in the neuritic plaques of Alzheimer's disease, activates astrocytes and enhances production and processing of beta-amyloid precursor protein (beta-APP). Activated astrocytes, overexpressing S100 beta, are a prominent feature of these neuritic plaques, and the neurite growth-promoting properties of S100 beta have been implicated in the formation of dystrophic neurites overexpressing beta-APP in neuritic plaques. These facts collectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100 beta and beta-APP overexpression and dystrophic neurite formation in Alzheimer's disease. To more directly assess this driver potential for IL-1, we analyzed IL-1 induction of S100 beta expression in vivo and in vitro, and of beta-APP expression in vivo. Synthetic IL-1 beta was injected into the right cerebral hemispheres of 13 rats. Nine additional rats were injected with phosphate-buffered saline, and seven rats served as uninjected controls. The number of astrocytes expressing detectable levels of S100 beta in tissue sections from IL-1-injected brains was 1.5 fold that of either control group (p < 0.01), while tissue S100 beta levels were approximately threefold that of controls (p < 0.05). The tissue levels of two beta-APP isoforms (approximately 130 and 135 kDa) were also significantly elevated in IL-1-injected brains (p < 0.05). C6 glioma cells, treated in vitro for 24 h with either IL-1 beta or IL-1 alpha, showed significant increases in both S100 beta and S100 beta mRNA levels. These results provide evidence that IL-1 upregulates both S100 beta and beta-APP expression, in vivo and vitro, and support the idea that overexpression of IL-1 in Alzheimer's disease drives astrocytic overexpression of S100 beta, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic beta-amyloid plaques.

Human brain S100 beta and S100 beta mRNA expression increases with age: pathogenic implications for Alzheimer's disease.

S100 beta is a neurite extension factor that has been implicated in the development of neuritic plaques in Alzheimer's disease. We analyzed the expression of S100 beta and its encoding mRNA, using immunohistochemistry, enzyme-linked immunosorbent assay, and Northern blot analysis, in postmortem brain tissue from 26 neurologically normal patients, aged 1-80 years. Tissue levels of S100 beta and S100 beta mRNA, as well as the number of S100 beta-immunoreactive (S100 beta +) astrocytes, increased with advancing age (r = 0.60, p = 0.008; r = 0.65, p = 0.007: and r = 0.73, p = 0.001, respectively). In patients more than 60 years old, the number of S100 beta + astrocytes and the tissue levels of S100 beta and S100 beta mRNA were significantly higher than those in patients less than 60 years of age (p = 0.001, p = 0.035, and p = 0.047, respectively). All of these values, however, were significantly less than those found in Alzheimer patients (p < 0.05 or better). Our findings, together with the known functions of S100 beta, suggest that age-related increases in S100 beta expression are important in the pathogenesis of Alzheimer's disease and may explain in part the increased incidence of this disease with advancing age.

Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy.

Neuritic sprouting and disturbances of calcium homeostasis are well described in epilepsy. S100 beta is an astrocyte-derived cytokine that promotes neurite growth and induces increases in levels of intracellular calcium in neurons. In sections of neocortex of surgically resected temporal lobe tissue from patients with intractable epilepsy, we found that the number of S100 beta-immunoreactive astrocytes was approximately threefold higher than that found in control patients (p < 0.001). These astrocytes were activated, i.e., enlarged, and had prominent processes. Temporal lobe tissue levels of S100 beta were shown by ELISA to be fivefold higher in 21 epileptics than in 12 controls (p < 0.001). The expression of the astrocyte intermediate filament protein, glial fibrillary acidic protein, was not significantly elevated in epileptics, suggesting a selective up-regulation of S100 beta expression. Our findings, together with established functions of S100 beta, suggest that this neurotrophic cytokine may be involved in the pathophysiology of epilepsy.