Neuroreport
-
7-Chlorokynurenic acid (7-Cl-KYNA) and 5,7-dichlorokynurenic acid (5,7-Cl2-KYNA) are of therapeutic interest as potent glycine/N-methyl-D-aspartate NMDA) receptor antagonists, but are excluded from brain by the blood-brain barrier. We examined whether these compounds could be delivered to brain through their respective precursors, L-4-chlorokynurenine (4-Cl-KYN) and L-4,6-dichlorokynurenine (4,6-Cl2-KYN), which are amino acids. 4-Cl-KYN was shown to be rapidly shuttled into the brain by the large neutral amino acid transporter of the blood-brain barrier (K(m) = 105 +/- 14 microM, Vmax = 16.9 +/- 2.3 nmol min-1 g-1) and to be converted intracerebrally to 7-Cl-KYNA. 4,6-Cl2-KYN also expressed affinity for the transporter, but four-fold less than that of 4-Cl-KYN. In summary, the results show that because of their facilitated uptake 4-Cl-KYN and 4,6-Cl2KYN might be useful prodrugs for brain delivery of glycine-NMDA receptor antagonists.
-
The inflammatory component of peripheral nerve injury may affect the development of local neuropathologic changes as well as the onset of hyperalgesia, the characteristic features of experimental neuropathic pain states. The goal of this study was to determine whether local sciatic injection of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha could reproduce the nociceptive behaviors and endoneurial pathology found following experimental nerve injuries. TNF injection caused significant thermal hyperalgesia and mechanical allodynia for 3 days post-injection in association with nerve edema, splitting of myelin lamellae with vacuolization, Schwann cell injury, fibroblast and macrophage activation, and phagocytosis of lipid debris. The data show that subperineurial injection of TNF proximal to peripheral sensory receptors generates the transient display of behaviors and endoneurial pathologies found in experimental painful nerve injury, and implicates local TNF in the pathologies of neuropathic pain.
-
As with any substance that interferes with nervous system functioning, anaesthetics are likely to have neural effects the duration of which extend beyond the acute loss of consciousness. Studies of recovery after anaesthesia have shown that physiological effects and psychomotor functions return to pre-anaesthesia levels within at most 90 min of the cessation of propofol administration. ⋯ We evaluated a range of cognitive tasks (short and long-term memory, attention, language comprehension and planning) up to 6 h after cessation of Propofol administration, and found that this set of cognitive functions was still depressed after 3 h, but had recovered by 6 h. The results suggest that, for their security, patients should be remain in a supervised environment for at least 3 h after propofol anaesthesia, and that oral information to patients within those 3 h should be avoided.
-
Murine gamma-aminobutyric acid type A (GABAA) receptor beta 1, beta 2, and beta 3 subunits were expressed in Xenopus oocytes and studied using the two electrode voltage clamp technique. Although all three beta-subunits were unresponsive to GABA when expressed as homomers, the intravenous general anaesthetics pentobarbital, etomidate and propofol induced currents in beta 2 and beta 3 homomers. The pentobarbital-induced currents in beta 3 homomers showed a dose dependence with an ED50 of 89 +/- 8.9 microM and a Hill coefficient of 0.94 +/- 0.08. ⋯ This current was also blocked by picrotoxin but was insensitive to the GABAA receptor antagonist bicuculline. These observations indicate that the full expression of the agonistic action of GABA requires the presence of an alpha-subunit, in contrast to the agonistic action of intravenous general anesthetics, where the presence of a beta2 or beta 3-subunit is sufficient. The difference in the agonistic action of intravenous anaesthetics among these highly homologous beta-subunits suggests that the beta-subunit homomeric receptors may be useful to further define the molecular sites of action of intravenous general anaesthetics and other functional domains on GABAA receptors.
-
Glutathione levels are decreased in the substantia nigra of patients with Parkinson's disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). ⋯ However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.