Targeting the kynurenine pathway as a potential strategy to prevent and treat Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly accounting for the vast majority of dementia. Recently, many studies have implicated the role of inflammatory response, especially neuroinflammatory response in the development and progression of AD. However, the underlying mechanism of how inflammatory response induces AD is unknown. Kynurenine pathway is a major route of the amino acid tryptophan catabolism, resulting in the production of nicotine adenine dinucleotide and other neuroactive intermediates: quinolinic acid (QA) and kynurenic acid (KA). QA exerts different toxic effects, including over-activation of N-methyl-d-aspartate (NMDA) receptor and excitotoxicity, synaptic dysfunction and neuronal death. On the other hand, KA is identified as the only endogenous NMDA receptor antagonist and could modulate neurotoxic effects of QA. We hypothesize that an activated kynurenine pathway induced by inflammatory cytokines would generate more neurotoxic metabolites, which could be closely related to the pathogenesis of AD in elderly patients. Moreover, some measures, which facilitate KA synthesis and reduce the formation of QA, may emerge as a new therapeutic strategy against AD.

A model for the preferential delivery of isoflurane to the spinal cord of the goat.

To identify the blood supply of the caprine central nervous system, six anaesthetised goats were perfused with coloured suspension into the brachiocephalic artery, the aorta, the iliac artery and the femoral artery. The subsequent distribution indicated that the brain and the main segments of the spinal cord were supplied by the brachiocephalic artery and aorta, respectively. Ten similarly anaesthetised goats then received emulsified isoflurane randomly via either the proximal part of the descending aorta (arterial group) or an ear vein (venous group). In the arterial group, the isoflurane partial pressure (P(iso)) in femoral arterial blood was almost double the P(iso) in jugular venous blood. The model showed that preferential delivery of isoflurane to the goat spinal cord in situ was possible and could be used for further research into the mechanisms of anaesthetic action, particularly factors affecting immobility.

[Preferential delivery of emulsified isoflurane to peripheral nerves in goats].

OBJECTIVE: To develop a new model for preferential delivery of isoflurane to peripheral nerves in goats, and to identify preliminarily volatile anesthetic action sites. METHODS: Eighteen goats were randomly and equally divided into arterial group, control group and venous group. In the arterial group, emulsified isoflurane was infused into the femoral artery of the goats to deliver isoflurane to the peripheral nerves. In the control group, 30% Intralipid which used as a solvent of emulsified isoflurane was infused via the femoral artery of the goats with the same infusing speed as that of the arterial group. In the venous group, emulsified isoflurane was infused via an ear peripheral vein. Minimum partial pressure (MPP), the partial pressure (Piso) of isoflurane in blood producing immobility in 50% of the goats exposed to noxious stimuli, was determined with an up-and-down method and a noxious stimulus by clamping the dew-claw of the hindlimbs of the goats in the arterial group and the control group, or the dew-claw of the hindlimb of the goats in the venous group. RESULTS: No isoflurane was found in the jugular and femoral veins of the goats in the control group, and normal nociceptive reflexeswere maintained. The MPP of the femoral vein of the goats from the control group did not differ from the MPP of the jugular vein of the goats from the arterial and venous groups. The MPP of femoral vein p was 7 times of that of jugular vein ](38.45 +/- 17. 01) mmHg vs. (5.82 +/- 2.32) mmHg, 1 mmHg = 0.1333 kPa, P < 0.05] in the goats from the arterial group, and 4 times of that of jugular vein in the goats from the venous group [(9.41 +/- 1.61) mmHg, P < 0.05]. The MPP of jugular vein in the goats from the arterial group was about half of that of the goats in the venous group. CONCLUSION: A new model of preferential delivery of isoflurane to the peripheral nerves in goats has been developed. Only Piso higher than that used in clinical anesthetic range has a significant anesthetic effect on peripheral nerves.

Reversible conduction block in isolated toad sciatic nerve by emulsified isoflurane.

BACKGROUND: Studies have shown that the local use of volatile anesthetics can produce local anesthetic effects. We designed this study to evaluate the characteristics of nerve conduction block of emulsified isoflurane (EI) and compare its nerve blockade with 1%lidocaine, by measuring compound nerve action potential (CNAP) parameters in isolated toad sciatic nerve. METHODS: One hundred isolated toad sciatic nerves were selected and randomly assigned to 10 groups of 10 each, administered 2% to 8% EI (v/v) (EI(8) group, etc.), 1% lidocaine, 30% Intralipid(R) (Huarui Pharmacy, Wuxi, Jiangsu, China), and Ringer solution (RS) for 10 minutes, respectively. All nerves were then washed and soaked with RS for 10 minutes and 30 minutes. The nerve conduction block effect was represented by CNAP parameters that were recorded by an extracellular recording technique per minute. RESULTS: The results showed that the negative amplitudes of CNAP were decreased by EI and lidocaine (P < 0.05), and the conduction velocities of CNAP were also decreased at some time points (D7-W3) (P < 0.05). After RS washing, the 2 parameters recovered gradually. The changes in the 2 parameters induced by EI had slower onset rates and faster recoveries than those produced by lidocaine (7 minutes vs 1 minute and 9 minutes vs 30 minutes). The nerve blockade induced by EI was dose dependent (P < 0.05), and the half maximal inhibition concentration of EI was 5.46%. CONCLUSIONS: EI produced completely reversible and dose-dependent nerve conduction inhibition, which had slower onset and faster recovery compared with those produced by lidocaine.

Further proof that the spinal cord, and not the brain, mediates the immobility produced by inhaled anesthetics.

BACKGROUND: Previous investigations indicate that the spinal cord, perhaps with a minor cerebral contribution, mediates the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation. The implications of these investigations may be limited by the trauma associated with their experimental methods (e.g., cardiopulmonary bypass or transection of the spinal cord). The present study avoided such trauma. METHODS: Thirty goats received emulsified isoflurane via either the initial section of the aorta (arterial group; preferential isoflurane delivery to the spinal cord) or an ear vein (venous group; equal delivery of isoflurane to the cord and brain). The authors determined the minimum partial pressure of isoflurane (the isoflurane partial pressure in the blood required to produce immobility in 50% of the goats exposed to a noxious stimulus). RESULTS: For the venous group, the minimum partial pressure in carotid versus femoral arterial blood (9.56 +/- 1.86 mmHg vs. 9.68 +/- 1.90 mmHg) did not differ. For the arterial group, the minimum partial pressure in carotid arterial blood was half that in femoral arterial blood (5.35 +/- 1.45 mmHg vs. 10.97 +/- 3.04 mmHg, P < 0.05). As these data show, the minimum partial pressure in femoral arterial blood did not differ for the arterial group versus the venous group. CONCLUSIONS: In this novel and minimally traumatic model, the anesthetic partial pressure delivered to the spinal cord governed the suppression of movement in response to noxious stimulation. The results indicate that the spinal cord is the primary mediator of immobility and that the brain plays little or no role.

[Model establishment for emulsified isoflurane delivered selectively to the goat spinal cord and preliminary research on the immobility mechanism of isoflurane].

OBJECTIVE: To develop a new model of preferentially delivering isoflurane to the goat spinal cord, and to explore preliminarily volatile anesthetic action sites. METHODS: Eighteen goats were randomly and equally divided into group artery and group vein. In group artery, emulsified isoflurane was infused into descending aorta for developing the model to deliver isoflurane to the goat spinal cord. In group vein, emulsified isoflurane was infused via the ear vein. After the end-tidal isoflurane concentration of 1 minimum alveolar concentration (MAC) was maintained for 20 min, the isoflurane partial pressures (P(iso)) in samples which were drawn from the femoral artery and the carotid artery were determined by a gas chromatography. RESULTS: In group vein, there was no statistical difference among all the P(iso). In group artery, the P(iso) of the femoral arterial blood was almost same as that in group vein, but the P(iso) of the carotid arterial blood was near half of that in group vein [(6.07 +/- 3.60) mmHg vs (10.21 +/- 2.41) mmHg, P < 0.05]. CONCLUSION: This new model permits preferentially to deliver the isoflurane to the in situ goat spinal cord, and the results support the importance of the spinal cord in suppressing nociceptive reflex under isoflurane anesthesia.

[Pathological changes in the testes of the rats with hypospadia induced by dichlorvos].

OBJECTIVE: To study the mechanism of dichlorvos leading to hypospadia of rats. METHODS: From the 12th to the 17th day of conception, 20 pregnant female rats (the experiment group) were given 10 mg/(kg x d) dichlorvos, while another 10 (the control group) administered 1.5 ml 0.9% NaCl/day. Out of 88 male newborns of the 20 experimental mother rats, 22 had hypospadia, while out of the 33 male newborns of the 10 controls, none had the problem. Five hypospadia newborns from the experiment group and another 5 normal ones from the control group were raised to sexual maturity, and then their testes were excised and embedded in paraffin, and the tissue sections were analyzed by regular HE staining and SP immunohistochemical staining with Calretinin. RESULTS: HE staining showed that the number of Leydig cells in the testis tissues of the hypospadia rats decreased significantly compared with the normal ones, but no change was observed either in the number or in the morphology of the seminiferous tubules. Moreover, the Calretinin positive Leydig cells were reduced dramatically in the testes of the hypospadia rats. CONCLUSION: Pregnant female rats, when exposed to dichlorvos, may cause reduction of testis Leydig cells in their male offsprings. Thus the probable mechanism of rat hypospadia induced by dichlorvos may lie in the decrease of the testosterone level caused by damage to Leydig cells from dichlorvos toxicity.