Deposition of amyloid fibrils in the brain is a histopathologic hallmark of Alzheimer disease (AD) and beta-amyloid protein (A beta), the principal component of amyloid fibrils, has been implicated in the neuropathogenesis of AD. In the present study, we first developed an in vitro model of A beta-induced neurodegeneration using human fetal brain-cell cultures and then tested the hypothesis that cytokines modulate A beta-induced neurodegeneration. When brain-cell cultures were exposed to A beta, marked neuronal loss (60% of neurons by microscopic assessment) and functional impairment (i.e., reduction in uptake of [3H]gamma-aminobutyric acid) were observed after 6 d of incubation. A beta-induced neurodegeneration was dose-dependent with maximal effect at 100 microM. Although interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha had a nominal effect, both the beta 1 and beta 2 isoforms of transforming growth factor-beta dose-dependently protected > 50% of neurons against A beta-induced injury. IL-4 also proved to be neuro-protective. A beta-induced neurodegeneration was accompanied by microglial cell proliferation and enhanced release of IL-1, IL-6, and TNF-alpha. These findings are consistent with the emerging concept that AD is an inflammatory disease and may lead to new therapeutic strategies aimed at reducing A beta-induced neurotoxicity.

Amyloid beta-Peptides↗

PubMedDate not supplied

Effects of high intravenous doses of dynorphin A(1-13) on tail flick latency and central nervous system histology in rats.

Dynorphin A(1-13) blocks opiate withdrawal in rats without producing dependence, and enhances analgesia in morphine-tolerant animals. Its potential use in humans is therefore of interest. Dynorphin A(1-13) has little toxicity when administered at modest doses IV but has been reported to cause hindlimb paralysis and necrosis of the spinal cord in rats, at the catheter tip, when administered intrathecally. To further evaluate its potential neurotoxicity, we administered dynorphin A(1-13) to rats at very high doses IV. Rats (n = 6-10 per group) received dynorphin A(1-13) as bolus IV doses of 5 mg/kg, or as continuous IV infusions of 40 mg/kg/day for 1 day, with saline controls. The appearance and behavior of all animals was normal. Tail flick latencies remained unchanged (p > 0.5). There were no histologic abnormalities of the spinal cord or brain when examined by light microscopy. Two additional groups received bolus injections of dynorphin A(1-13) 50 or 100 mg/kg IV. Animals receiving 50 mg/kg showed cutaneous flushing, labored respirations, and decreased spontaneous movement, which resolved within 10 min. Histology at 1 week was normal. All six animals receiving 100 mg/kg convulsed and died within minutes. Three animals that received dynorphin A(1-13) 40 mg/kg/day for 7 days had normal behavior and histology. We conclude that the previously observed neurotoxicity of intrathecally administered dynorphin A(1-13) is a local effect that does not occur when dynorphin A(1-13) is administered IV, even at very high doses.

Analgesics, Opioid↗

PubMedDate not supplied

Self-inflicted bite marks in battered child syndrome.

Examination of a child abuse victim revealed bite marks on both arms. These lesions are usually pursued as a clue to the identity of the specific perpetrator. We demonstrated that the bite was from the victim. Importance of this phenomenon in evaluation of bite injuries is discussed.

Battered Child Syndrome↗