To determine if impaired energy metabolism might contribute to some aspects of Alzheimer disease (AD), including the vulnerability of the CA1 region of the hippocampal formation and the altered cytoskeleton evident in neurofibrillary tangles, we examined the effects of metabolic poisons on neuronal damage and cytoskeletal disruption in the hippocampal formation. Intrahippocampal injection of 3-nitropropionic acid (3-NP) and malonic acid resulted in neuronal death, particularly in CA1. Cytoskeletal disruption included loss of dendritic MAP2, but sparing of axonal τ. MK-801 (a noncompetitive NMDA receptor antagonist) did not atenuate the lesions produced by intrahippocampal injection of malonate. MK-801, however, was effective against intrastriatal malonate. Acute systemic 3-NP resulted in neuronal damage and cytoskeletal disruption in the CA1 region of the hippocampal formation, including an extensive loss of MAP2 immuno-reactivity, but sparing of τ. The neuronal loss in CA1 was delayed as compared to striatum. Chronic intraventricular infusion of 3-NP produced a different pattern of neuronal damage. Loss of τ-1 immuno-reactivity was observed in CA3 and CA1 s. oriens, whereas MAP2 immunostaining was preserved. These results demonstrate that chronic and acute administration of metabolic inhibitors produce distinct patterns of neuronal damage and cytoskeletal disruption. The results further suggest a differential involvement of the NMDA receptor in malonate-induced neuronal damage in striatum as compared to the hippocampus. The pattern of neuronal damage and cytoskeletal disruption observed following acute metabolic impairment resembled some aspects of neurofibrillary pathology in AD, but did not result in τ hyperphosphorylation. 相似文献
Summary— To investigate if the functional alterations observed in resistance arteries of spontaneously hypertensive rats (SHRs) were also present at the coronary level, in vitro experiments were performed in mesenteric resistance arteries (MRA) and in right (RIC) and left interventricular coronary (LIC) arteries taken from 15–25-week-old SHR and age-matched Wistar Kyoto rats WKYs. Using a passive extension protocol, internal diameters corresponding to 100 mmHg intraluminal pressure (D100) were determined and vessels were set up to a normalized internal diameter (0.9 D100). SHR mesenteric resistance arteries had a significantly smaller diameter compared to WKY arteries, whereas both types of SHR coronary arteries had a greater diameter compared to those of WKY rats. In arteries in the absence of contracting agonist, nitro-L-arginine (NOLA, 100 μM) induced a progressive rise in basal tone, which could be reversed by subsequent addition of L-arginine (100 μM) but not D-arginine (100 μM). When expressed as percent of maximal contractions induced by agonists (noradrenaline, NA [10 μM] in MRA; serotonin, 5-HT [10 μM], in RIC and LIC), these contractions were significantly stronger in WKY compared to SHR coronary and mesenteric resistance arteries. In NA-precontracted MRA and 5HT-precontracted coronary arteries in the presence of indomethacin (10 μM), the magnitude of acetylcholine-induced maximal relaxations (expressed as percent of maximal contractions induced by agonists) was greater in WKY compared to SHR arteries. After a 30-min incubation period, NOLA (100 μM) completely inhibited relaxations induced by acetylcholine (0.01–10 μM) in all types of precontracted arteries. Subsequent additions of sodium nitroprusside, (SNP, 10 μM) induced complete relaxations in all preparations. These results show that a basal release of NO or NO-like compound by endothelial cells is present in isolated mesenteric resistance and coronary arteries of WKY rats and SHRs. The contribution of endothelium-derived relaxing factor-nitric oxide (EDRF-NO) to arterial tone was lower in MRA compared to coronary arteries in both strains and in SHR compared to WKY arteries. In the SHR preparations, the impaired relaxation induced by acetylcholine appeared to be due to a functional alteration of the endothelium in the presence of normal reactivity of the smooth muscle cells. 相似文献
Background: There is considerable controversy regarding the role of subarachnoid 5% hyperbaric lidocaine in the syndrome transient radicular irritation (TRI). This randomized, double-blinded, prospective study was designed to determine the incidence of TRI and identify factors possibly contributing to its development.
Methods: One hundred fifty-nine ASA physical status 1 or 2 patients undergoing outpatient knee arthroscopy or unilateral inguinal hernia repair were prospectively randomized to receive spinal anesthesia with 5% hyperbaric lidocaine with epinephrine (60 mg with 0.2 mg epinephrine for arthroscopy or 75 mg with 0.2 mg epinephrine for hernia repair), 2% isobaric lidocaine without epinephrine (60 mg for arthroscopy or 75 mg for hernia repair), or 0.75% hyperbaric bupivacaine without epinephrine (7.5 mg for arthroscopy or 9.0 mg for hernia repair) in a double-blinded fashion. On the 3rd postoperative day, patients were contacted by a blinded investigator and questioned regarding the incidence of postoperative complications including TRI, defined as back pain with radiation down one or both buttocks or legs occurring within 24 h after surgery. Postoperatively, time from injection to block resolution, ambulation, voiding, and ready for discharge were recorded by a postanesthesia care unit nurse blinded to the group assignment.
Results: The incidence of TRI was greater in patients receiving lidocaine than in those receiving bupivacaine (16% vs. 0%; P = 0.003). There was no difference in the incidence of TRI between the patients receiving 59% hyperbaric lidocaine with epinephrine and those receiving 2% isobaric lidocaine without epinephrine (16% vs. 16%; P = 0.98). The incidence of TRI was greater in patients undergoing arthroscopy than in those undergoing hernia repair (13% vs. 5%; P = 0.04). There was no difference in discharge times in patients receiving bupivacaine versus those receiving hyperbaric lidocaine with epinephrine (292 vs. 322 min; P = 0.61). 相似文献