Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.

BACKGROUND: Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. METHODS: A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition. RESULTS: GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks. CONCLUSIONS: GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.

Combined Supplementation with Glycine and Tryptophan Reduces Purine-Induced Serum Uric Acid Elevation by Accelerating Urinary Uric Acid Excretion: A Randomized, Single-Blind, Placebo-Controlled, Crossover Study.

The authors previously confirmed the serum uric acid-lowering effects of the combination of glycine and tryptophan in subjects with mild hyperuricemia. This study examined whether combined supplementation with glycine and tryptophan suppressed the elevation in serum uric acid levels caused by purine ingestion and accelerated urinary uric acid excretion in subjects with lower urate excretion using a randomized, single-blind, placebo-controlled, crossover clinical trial design. Healthy Japanese adult males with lower urate excretion ingested water containing purines in addition to dextrin (placebo), tryptophan, glycine, or a glycine and tryptophan mixture. The combined supplementation with glycine and tryptophan significantly reduced the elevated serum uric acid levels after purine ingestion. Glycine alone and in combination with tryptophan significantly increased urinary uric acid excretion and urate clearance compared with the effects of the placebo. Urinary pH increased by the ingestion of the mixture. These results suggested that the improved water solubility of uric acid due to increased urinary pH contributed to the increase of urinary uric acid excretion.

Glycine administration attenuates progression of dystrophic pathology in prednisolone-treated dystrophin/utrophin null mice.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by progressive muscle wasting and weakness and premature death. Glucocorticoids (e.g. prednisolone) remain the only drugs with a favorable impact on DMD patients, but not without side effects. We have demonstrated that glycine preserves muscle in various wasting models. Since glycine effectively suppresses the activity of pro-inflammatory macrophages, we investigated the potential of glycine treatment to ameliorate the dystrophic pathology. Dystrophic mdx and dystrophin-utrophin null (dko) mice were treated with glycine or L-alanine (amino acid control) for up to 15 weeks and voluntary running distance (a quality of life marker and strong correlate of lifespan in dko mice) and muscle morphology were assessed. Glycine increased voluntary running distance in mdx mice by 90% (P < 0.05) after 2 weeks and by 60% (P < 0.01) in dko mice co-treated with prednisolone over an 8 week treatment period. Glycine treatment attenuated fibrotic deposition in the diaphragm by 28% (P < 0.05) after 10 weeks in mdx mice and by 22% (P < 0.02) after 14 weeks in dko mice. Glycine treatment augmented the prednisolone-induced reduction in fibrosis in diaphragm muscles of dko mice (23%, P < 0.05) after 8 weeks. Our findings provide strong evidence that glycine supplementation may be a safe, simple and effective adjuvant for improving the efficacy of prednisolone treatment and improving the quality of life for DMD patients.

Comparative evaluation of two glycine transporter 1 radiotracers [11C]GSK931145 and [18F]MK-6577 in baboons.

Glycine transporter type-1 (GlyT1) has been proposed as a target for drug development for schizophrenia. PET imaging with a GlyT1 specific radiotracer will allow for the measurement of target occupancy of GlyT1 inhibitors, and for in vivo investigation of GlyT1 alterations in schizophrenia. We conducted a comparative evaluation of two GlyT1 radiotracers, [(11) C]GSK931145, and [(18) F]MK-6577, in baboons. Two baboons were imaged with [(11) C]GSK931145 and [(18) F]MK-6577. Blocking studies with GSK931145 (0.3 or 0.2 mg/kg) were conducted to determine the level of tracer specific binding. [(11) C]GSK931145 and [(18) F]MK-6577 were synthesized in good yield and high specific activity. Moderately fast metabolism was observed for both tracers, with ∼ 30% of parent at 30 min post-injection. In the brain, both radiotracers showed good uptake and distribution profiles consistent with regional GlyT1 densities. [(18) F]MK-6577 displayed higher uptake and faster kinetics than [(11) C]GSK931145. Time activity curves were well described by the two-tissue compartment model. Regional volume of distribution (VT ) values were higher for [(18) F]MK-6577 than [(11) C]GSK931145. Pretreatment with GSK931145 reduced tracer uptake to a homogeneous level throughout the brain, indicating in vivo binding specificity and lack of a reference region for both radiotracers. Linear regression analysis of VT estimates between tracers indicated higher specific binding for [(18) F]MK-6577 than [(11) C]GSK931145, consistent with higher regional binding potential (BPND ) values of [(18) F]MK-6577 calculated using VT from the baseline scans and non-displaceable distribution volume (VND ) derived from blocking studies. [(18) F]MK-6577 appears to be a superior radiotracer with higher brain uptake, faster kinetics, and higher specific binding signals than [(11) C]GSK931145.

Re-Emergent Inhibition of Cochlear Inner Hair Cells in a Mouse Model of Hearing Loss.

Hearing loss among the elderly correlates with diminished social, mental, and physical health. Age-related cochlear cell death does occur, but growing anatomical evidence suggests that synaptic rearrangements on sensory hair cells also contribute to auditory functional decline. Here we present voltage-clamp recordings from inner hair cells of the C57BL/6J mouse model of age-related hearing loss, which reveal that cholinergic synaptic inputs re-emerge during aging. These efferents are functionally inhibitory, using the same ionic mechanisms as do efferent contacts present transiently before the developmental onset of hearing. The strength of efferent inhibition of inner hair cells increases with hearing threshold elevation. These data indicate that the aged cochlea regains features of the developing cochlea and that efferent inhibition of the primary receptors of the auditory system re-emerges with hearing impairment. SIGNIFICANCE STATEMENT: Synaptic changes in the auditory periphery are increasingly recognized as important factors in hearing loss. To date, anatomical work has described the loss of afferent contacts from cochlear hair cells. However, relatively little is known about the efferent innervation of the cochlea during hearing loss. We performed intracellular recordings from mouse inner hair cells across the lifespan and show that efferent innervation of inner hair cells arises in parallel with the loss of afferent contacts and elevated hearing threshold during aging. These efferent neurons inhibit inner hair cells, raising the possibility that they play a role in the progression of age-related hearing loss.

POSTOPERATIVE COMPLICATIONS WITH GLYCINE AND STERILE DISTILLED WATER AFTER TRANSURETHRAL RESECTION OF PROSTATE.

BACKGROUND: Transurethral resection of prostate (TURP) is considered the gold standard for the surgical treatment of BPH. Irrigant fluid absorption by the patient is a potentially serious complication of TURP and can lead to dilutional hyponatremia and TURP syndrome. Other common complications of TURP include urinary tract infection and secondary haemorrhage. The objective of this study was to compare the frequency of postoperative complications (Urinary Tract infection and dilutional hyponatremia) between 1.5% glycine and sterile distilled water used as irrigant in BPH patients after TURP. METHODS: This randomized controlled trial was conducted in department of Urology, PIMS Islamabad, from August 2013 to February 2014. A total of 170 adult male patients between 50-80 years of age undergoing TURP with prostate volume more than 30cc on ultrasound. 85 patients each were randomly allocated to two groups. In group-A, glycine was used as irrigan,t solution during TURP while in group-B distilled water was used. Serum sodium levels were measured at 6th postoperative hour to look for dilutional hyponatremia. On the 15th postoperative day they were inquired about any clinical features of urinary tract infection. Also urine routine examination was performed to look for the presence of WBCs in the urine. RESULTS: Post-operative dilutional hyponatremia was observed in 13 (15.3%) patients in Group A and in 10 (11.8%) patients in group-B. The difference between both the groups being nonsignificant (p-value=0.501).Frequency of postoperative urinary tract infection on 15th postoperative day in group-A was 23(27.1%) while in group-B it was 16 (18.8%), the difference among both the groups being insignificant (p-value=0.202). CONCLUSION: Although the frequency of postoperative complications like UTI and dilutional hyponatremia was less with sterile distilled water, yet, the difference was statistically not significant.

In vivo coincidence detection in mammalian sound localization generates phase delays.

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.

Electrophysiological biomarkers of neuromodulatory strategies to recover motor function after spinal cord injury.

The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation [electrical enabling motor control (eEmc)] and/or administration of pharmacological agents [pharmacological enabling motor control (fEmc)] when combined with motor training. We hypothesized that the characteristics of the spinally evoked potentials after chronic administration of both strychnine and quipazine under the influence of eEmc during standing and stepping can be used as biomarkers to predict successful motor performance. To test this hypothesis we trained rats to step bipedally for 7 wk after paralysis and characterized the motor potentials evoked in the soleus and tibialis anterior (TA) muscles with the rats in a non-weight-bearing position, standing and stepping. The middle responses (MRs) to spinally evoked stimuli were suppressed with either or both drugs when the rat was suspended, whereas the addition of either or both drugs resulted in an overall activation of the extensor muscles during stepping and/or standing and reduced the drag duration and cocontraction between the TA and soleus muscles during stepping. The administration of quipazine and strychnine in concert with eEmc and step training after injury resulted in larger-amplitude evoked potentials [MRs and late responses (LRs)] in flexors and extensors, with the LRs consisting of a more normal bursting pattern, i.e., randomly generated action potentials within the bursts. This pattern was linked to more successful standing and stepping. Thus it appears that selected features of the patterns of potentials evoked in specific muscles with stimulation can serve as effective biomarkers and predictors of motor performance.

Fluid volume kinetics of dilutional hyponatremia; a shock syndrome revisited.

OBJECTIVE: To evaluate whether the pathophysiology of shock syndromes can be better understood by comparing central hemodynamics with kinetic data on fluid and electrolyte shifts. METHODS: We studied the dilutional hyponatremic shock that developed in response to overhydration with electrolyte-free irrigating fluid - the so-called 'transurethral resection syndrome' - by comparing cardiac output, arterial pressures, and volume kinetic parameters in 17 pigs that were administered 150 ml/kg of either 1.5% glycine or 5% mannitol by intravenous infusion over 90 minutes. RESULTS: Natriuresis appeared to be the key factor promoting hypovolemic hypotension 15-20 minutes after fluid administration ended. Excessive sodium excretion, due to osmotic diuresis caused by the irrigant solutes, was associated with high estimates of the elimination rate constant (k10) and low or negative estimates of the rate constant describing re-distribution of fluid to the plasma after translocation to the interstitium (k21). These characteristics indicated a high urinary flow rate and the development of peripheral edema at the expense of plasma volume and were correlated with reductions in cardiac output. The same general effects of natriuresis were observed for both irrigating solutions, although the volume of infused 1.5% glycine had a higher tendency to enter the intracellular fluid space. CONCLUSION: Comparisons between hemodynamics and fluid turnover showed a likely sequence of events that led to hypovolemia despite intravenous administration of large amounts of fluid.

Fluid volume kinetics of dilutional hyponatremia; a shock syndrome revisited

OBJECTIVE: To evaluate whether the pathophysiology of shock syndromes can be better understood by comparing central hemodynamics with kinetic data on fluid and electrolyte shifts. METHODS: We studied the dilutional hyponatremic shock that developed in response to overhydration with electrolyte-free irrigating fluid - the so-called ‘transurethral resection syndrome' - by comparing cardiac output, arterial pressures, and volume kinetic parameters in 17 pigs that were administered 150 ml/kg of either 1.5% glycine or 5% mannitol by intravenous infusion over 90 minutes. RESULTS: Natriuresis appeared to be the key factor promoting hypovolemic hypotension 15-20 minutes after fluid administration ended. Excessive sodium excretion, due to osmotic diuresis caused by the irrigant solutes, was associated with high estimates of the elimination rate constant (k10) and low or negative estimates of the rate constant describing re-distribution of fluid to the plasma after translocation to the interstitium (k21). These characteristics indicated a high urinary flow rate and the development of peripheral edema at the expense of plasma volume and were correlated with reductions in cardiac output. The same general effects of natriuresis were observed for both irrigating solutions, although the volume of infused 1.5% glycine had a higher tendency to enter the intracellular fluid space. CONCLUSION: Comparisons between hemodynamics and fluid turnover showed a likely sequence of events that led to hypovolemia despite intravenous administration of large amounts of fluid. .

Potentiation of NMDA receptors by Withania somnifera on hippocampal CA1 pyramidal neurons.

In Ayurveda,Withania somnifera (WS) is used as a medicine to maintain mental and physical health as well as to enhance memory. In this study, the methanolic extract of WS(mWS) was tested for its electrical influence on hippocampal CA1 pyramidal neurons using a patch clamp technique. In current clamp mode under a high chloride pipette solution, mWS (400 ng/µl) induced remarkable membrane depolarization (9.75 ± 2.54 mV, n = 6) of CA1 neurons. The mWS-induced depolarization was dose-dependent, reproducible, and persistent in the presence of 0.5 µM tetrodotoxin (TTX, 10.17 ± 0.04 mV, n = 6). In voltage clamp mode (holding potential = -60 mV), mWS induced a dose-dependent non-desensitizing inward current that persisted in the presence of TTX (0.5 µM), suggesting that the response induced by mWS was purely a postsynaptic event. Interestingly, these inward currents were partially blocked by strychnine, a glycine receptor blocker. Further, mWS potentiated the NMDA response in hippocampal CA1 neurons at low concentrations. Overall, these results suggest that there are compounds in WS with possible glycine mimetic activities, which may be potential targets for inducing memory consolidation in hippocampal CA1 neurons.

Glycine treatment of the risk syndrome for psychosis: report of two pilot studies.

Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium-to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.

Orexin neurons receive glycinergic innervations.

Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM) sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2)-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.

Beta-asarone inhibits synaptic inputs to airway preganglionic parasympathetic motoneurons.

Therapeutic application of Asarum, a herbal medicine that has been used for centuries, reportedly causes acute respiratory disturbance. The responsible constituents, the sites of action, and the mechanisms involved in this side effect are unclear. We investigated the effects of ß-asarone, a volatile constituent of Asarum, on neurotransmission in the medullary respiratory neuronal network using extracellular recording of the rhythmic hypoglossal activity and voltage clamp recordings of the postsynaptic activity of the airway preganglionic parasympathetic motoneurons (APPMs) in vitro. ß-Asarone caused progressive decreases in the duration and area of the hypoglossal bursts in a concentration-dependent manner. The frequency and amplitude of the bursts were initially unaltered or temporarily increased, but were then inhibited progressively after prolonged exposure. As with the inhibition of the hypoglossal bursts, the tonic and the phasic excitatory and inhibitory postsynaptic currents in the APPMs were attenuated. These data suggest that the Asarum-caused acute respiratory disturbance involves ß-asarone-induced inhibition of neurotransmission in the medullary respiratory neuronal network.

Pharmacological evaluation of a novel assay for detecting glycine transporter 1 inhibitors and their antipsychotic potential.

Multiple lines of evidence support the notion that hypofunction of glutamatergic neurotransmission is involved in the pathophysiology of schizophrenia. Moreover, glycine and glycine modulators have beneficial effects in patients with schizophrenia, particularly when added on to existing therapy. As glycine is an obligatory co-agonist at the NR1 subunit of the NMDA receptor, blockade of glycine uptake at the glycine transporter type-1 (GlyT1) can enhance low glutamatergic tone. L-687,414 is an antagonist at the glycine modulatory site of the NMDA complex and, behaviorally, increases locomotion. A series of GlyT1 inhibitors along with other psychoactive compounds were examined for their ability to enhance or inhibit the action of L-687,414. GlyT1 inhibitors and the other compounds were examined initially for effects on [(3)H]-glycine uptake in CHO cells expressing hGlyT1b cDNA and for their ability to displace the NMDA-glycine site ligand [(3)H]-L-689,560 from isolated rat forebrain membrane preparations. The in vivo activity of these compounds was determined in mice by measuring their ability to prevent L-687,414-induced hyperlocomotion. GlyT1 inhibitors blocked [(3)H]-glycine uptake in cells expressing the human transporter; other compounds had little or no activity. None of the compounds had affinity for the glycine site of the NMDA receptor complex. Hyperlocomotion induced by L-687,414 was dose-dependently reduced by GlyT1 inhibitors and antipsychotic drugs but not by morphine, fluoxetine or a moderate dose of diazepam. Therefore, this behavioral approach can reliably detect GlyT1 inhibitors which, in turn, may have some activity in common with drugs having antipsychotic effects.

Transurethral resection of prostate: a comparison of standard monopolar versus bipolar saline resection.

INTRODUCTION: Transurethral resection syndrome is an uncommon but potentially life threatening complication. Various irrigating solutions have been used, normal saline being the most physiological. The recent availability of bipolar cautery has permitted the use of normal saline irrigation. MATERIAL AND METHODS: In a randomized prospective study, we compared the safety and efficacy of bipolar cautery (using 0.9% normal saline irrigation) versus conventional monopolar cautery (using 1.5% glycine irrigation). Pre and postoperative hemoglobin (Hb) and hematocrit values were compared. Hemodynamics and arterial oxygen saturation were monitored throughout the study. Safety end points were changes in serum electrolytes, osmolarity and Hb/PCV (packed cell volume). Efficacy parameters were the International Prostate Symptom Score (IPSS) and Qmax (maximum flow rate in mL/sec) values. RESULTS: Mean preoperative prostate size on ultrasound was 60 +/- 20cc. Mean resected weight was 17.6 +/- 10.8 g (glycine) and 18.66 +/- 12.1 g (saline). Mean resection time was 56.76 +/- 14.51 min (glycine) and 55.1 +/- 13.3 min (saline). The monopolar glycine group showed a greater decline in serum sodium and osmolarity (4.12 meq/L and 5.14 mosmol/L) compared to the bipolar saline group (1.25 meq/L and 0.43 mosmol/L). However, this was not considered statistically significant. The monopolar glycine group showed a statistically significant decline in Hb and PCV (0.97 gm %, 2.83, p < 0.005) as compared to the bipolar saline group (0.55 gm % and 1.62, p < 0.05). Patient follow- up (1,3,6 and 12 months postoperatively) demonstrated an improvement in IPSS and Qmax in both the groups. CONCLUSION: We concluded that bipolar transurethral resection of prostate is clinically comparable to monopolar transurethral resection of prostate with an improved safety profile. However, larger number of patients with longer follow up is essential.

Transurethral resection of prostate: a comparison of standard monopolar versus bipolar saline resection

INTRODUCTION: Transurethral resection syndrome is an uncommon but potentially life threatening complication. Various irrigating solutions have been used, normal saline being the most physiological. The recent availability of bipolar cautery has permitted the use of normal saline irrigation. MATERIAL AND METHODS: In a randomized prospective study, we compared the safety and efficacy of bipolar cautery (using 0.9 percent normal saline irrigation) versus conventional monopolar cautery (using 1.5 percent glycine irrigation). Pre and postoperative hemoglobin (Hb) and hematocrit values were compared. Hemodynamics and arterial oxygen saturation were monitored throughout the study. Safety end points were changes in serum electrolytes, osmolarity and Hb/PCV (packed cell volume). Efficacy parameters were the International Prostate Symptom Score (IPSS) and Qmax (maximum flow rate in mL/sec) values. RESULTS: Mean preoperative prostate size on ultrasound was 60 ± 20cc. Mean resected weight was 17.6 ± 10.8 g (glycine) and 18.66 ± 12.1 g (saline). Mean resection time was 56.76 ± 14.51 min (glycine) and 55.1 ± 13.3 min (saline). The monopolar glycine group showed a greater decline in serum sodium and osmolarity (4.12 meq/L and 5.14 mosmol/L) compared to the bipolar saline group (1.25 meq/L and 0.43 mosmol/L). However, this was not considered statistically significant. The monopolar glycine group showed a statistically significant decline in Hb and PCV (0.97 gm percent, 2.83, p < 0.005) as compared to the bipolar saline group (0.55 gm percent and 1.62, p < 0.05). Patient follow- up (1,3,6 and 12 months postoperatively) demonstrated an improvement in IPSS and Qmax in both the groups. CONCLUSION: We concluded that bipolar transurethral resection of prostate is clinically comparable to monopolar transurethral resection of prostate with an improved safety profile. However, larger number of patients with longer follow up is essential.

Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia.

BACKGROUND: The general anesthetic gas xenon is neuroprotective and is undergoing clinical trials as a treatment for ischemic brain injury. A small number of molecular targets for xenon have been identified, the N-methyl-D-aspartate (NMDA) receptor, the two-pore-domain potassium channel TREK-1, and the adenosine triphosphate-sensitive potassium channel (KATP). However, which of these targets are relevant to acute xenon neuroprotection is not known. Xenon inhibits NMDA receptors by competing with glycine at the glycine-binding site. We test the hypothesis that inhibition of the NMDA receptor at the glycine site underlies xenon neuroprotection against hypoxia-ischemia. METHODS: We use an in vitro model of hypoxia-ischemia to investigate the mechanism of xenon neuroprotection. Organotypic hippocampal brain slices from mice are subjected to oxygen-glucose deprivation, and injury is quantified by propidium iodide fluorescence. RESULTS: We show that 50% atm xenon is neuroprotective against hypoxia-ischemia when applied immediately after injury or after a delay of 3 h after injury. To validate our method, we show that neuroprotection by gavestinel is abolished when glycine is added, confirming that NMDA receptor glycine site antagonism underlies gavestinel neuroprotection. We then show that adding glycine abolishes the neuroprotective effect of xenon, consistent with competitive inhibition at the NMDA receptor glycine site mediating xenon neuroprotection. CONCLUSIONS: We show that xenon neuroprotection against hypoxia- ischemia can be reversed by increasing the glycine concentration. This is consistent with competitive inhibition by xenon at the NMDA receptor glycine site, playing a significant role in xenon neuroprotection. This finding may have important implications for xenon's clinical use as an anesthetic and neuroprotectant.

Functional role of GABAergic and glycinergic inhibition in the intermediate nucleus of the lateral lemniscus of the big brown bat.

The intermediate nucleus of the lateral lemniscus (INLL) is a major input to the inferior colliculus (IC), the auditory midbrain center where multiple pathways converge to create neurons selective for specific temporal features of sound. However, little is known about how INLL processes auditory information or how it contributes to integrative processes at the IC. INLL receives excitatory projections from the cochlear nucleus and inhibitory projections from the medial nucleus of the trapezoid body (MNTB), so it must perform some form of integration. To address the question of what role inhibitory synaptic inputs play in the INLL of the big brown bat (Eptesicus fuscus), we recorded sound-evoked responses of single neurons and iontophoretically applied bicuculline to block GABA(A) receptors or strychnine to block glycine receptors. Neither bicuculline nor strychnine had a consistent effect on response latency or frequency response areas. Bicuculline increased spike counts and response durations in most units, suggesting that GABAergic input suppressed the late part of the response and provided some gain control. Strychnine reduced the responses of some units with sustained discharge patterns to one or a few spikes at stimulus onset, but increased others. INLL is the only part of the auditory system where reduced responsiveness has been seen in vivo while blocking glycine. However, in vitro studies in the MNTB suggest that glycine can be facilitatory, possibly through presynaptic action. These results show that GABA consistently reduces spike counts and response durations, whereas glycine is suppressive in some INLL neurons but facilitatory in others.

Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABA(A) receptor (GABA(A)R) agonist that preferentially activates delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs). To clarify the role of delta-GABA(A)Rs in mediating the sedative actions of THIP, we utilized mice lacking the alpha(1)- or delta-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of -60 mV. Application of bicuculline to wild-type (WT) VB neurones revealed a GABA(A)R-mediated tonic current of 92 +/- 19 pA, which was greatly reduced (13 +/- 5 pA) for VB neurones of delta(0/0) mice. Deletion of the delta- but not the alpha(1)-subunit dramatically reduced the THIP (1 mum)-induced inward current in these neurones (WT, -309 +/- 23 pA; delta(0/0), -18 +/- 3 pA; alpha(1) (0/0), -377 +/- 45 pA). Furthermore, THIP selectively decreased the excitability of WT and alpha(1) (0/0) but not delta(0/0) VB neurones. THIP did not affect the properties of miniature inhibitory post-synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose-dependent manner. The effect of THIP on rotarod performance was blunted for delta(0/0) but not alpha(1) (0/0) mice. We previously reported that deletion of the alpha(1)-subunit abolished synaptic GABA(A) responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic delta-GABA(A)Rs vs. synaptic alpha(1)-subunit-containing GABA(A)Rs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.