Antistress and adaptogenic activity of lecithin supplementation

OBJECTIVE: Investigation of lecithin administration in rats for its antistress and adaptogenic activity. DESIGN: Lecithin was administered orally (1 mg/g body weight) to rats 0.5 hour, 1.5 hours, 3.0 hours, and 6.0 hours prior to cold (5 degrees C)-hypoxia (428 mm Hg)-restraint (C-H-R) exposure and serum choline estimation. The rectal temperature (T(rec)) of the rats was monitored during the exposure and the recovery periods. The time for decrease of T(rec) to 23 degrees C and its recovery to 37 degrees C were used as indices of antistress and adaptogenic activity. RESULTS: Lecithin administration 3-6 hours prior to C-H-R exposure was found to have significant adaptogenic activity that correlated with increased serum choline levels. Lecithin administration prior to C-H-R exposure increased the stress tolerance of the rats by delaying the time for decrease of T(rec) to 23 degrees C during C-H-R exposure. It also helped shorten poststress recovery as observed by decreased time to attain T(rec) of 37 degrees C from C-H-R-induced hypothermia (T(rec), 23 degrees C). CONCLUSIONS: The results suggested that lecithin supplementation acted as an antistress and adaptogenic functional food. It improved resistance during C-H-R exposure and enhanced recovery from hypothermia.     

Antiprotozoan and Antiviral Activities of Non-cytotoxic Truncated and Variant Analogues of Mussel Defensin

We previously reported the crucial role displayed by loop 3of defensin isolated from the Mediterranean mussel, Mytilusgalloprovincialis, in antibacterial and antifungal activities.We now investigated antiprotozoan and antiviral activities ofsome previously reported fragments B, D, E, P and Q. Two fragments(D and P) efficiently killed Trypanosoma brucei (ID₅₀ 4–12µM) and Leishmania major (ID₅₀ 12–45 µM) ina time/dose-dependent manner. Killing of T. brucei started asearly as 1 h after initiation of contact with fragment D andreached 55% mortality after 6 h. Killing was temperature dependentand a temperature of 4°C efficiently impaired the abilityto kill T. brucei. Fragments bound to the entire external epitheliumof T. brucei. Prevention of HIV-1 infestation was obtained onlywith fragments P and Q at 20 µM. Even if fragment P wasactive on both targets, the specificity of fragments D and Qsuggest that antiprotozoan and antiviral activities are mediatedby different mechanisms. Truncated sequences of mussel defensin,including amino acid replacement to maintain 3D structure andincreased positive net charge, also possess antiprotozoan andantiviral capabilities. New alternative and/or complementaryantibiotics can be derived from the vast reservoir of naturalantimicrobial peptides (AMPs) contained in marine invertebrates.     

Comparative Electropharmacological Actions of Some Constituents from Ginkgo biloba Extract in Guinea-pig Ventricular Cardiomyocytes

Effects of the constituents from Ginkgo biloba extract (GBE)on the action potentials and the ionic currents in guinea pigventricular cardiomyocytes were investigated using whole-celland current-clamp techniques. The constituents, ginkgolidesA, B, C and quercetin, had depressant effects at 0.1–3µMon the action potential configuration. Ginkgolide A (1–3µM) prolonged the action potential (action potential duration:APD) at 75% and 90% repolarizations (APD₇₅ and APD₉₀). However,ginkgolides B and C at low concentrations prolonged APD, butat higher concentrations (>1 µM) shortened APD. Quercetinat 3 µM prolonged the APD, but not at the lower concentrations.These constituents also inhibited the V_max. The resting potentialwas unaffected. In voltage-clamp experiments, ginkgolides Aand B (0.1–3 µM) markedly and concentration-dependentlyincreased the Ca²⁺ current (I_Ca) and the delayed rectifier K⁺current (I_K), and decreased the inwardly rectifying K⁺ current(I_K1). On the other hand, ginkgolide C failed to affect theI_Ca but increased the I_K by 14.0 ± 2.3% (n = 6, P <0.05) at 1 µM. Quercetin inhibited I_Ca, and enhanced I_Kbut decreased I_K1. These responses to the constituents werealmost reversible (80–90% of control) after a 10- to 20-minwashout. These results indicate that even at acute administrations,these constituents produce the effective actions on the APDand the underlying ionic currents in cardiomyocytes. Each constituentdoes not exhibit a uniform response, although GBE acts as anet.     

Enhanced thermogenesis in rats by a composite Indian herbal preparation-I and its mechanism of action.

OBJECTIVE: A composite Indian herbal preparation-I (CIHP-I) containing ingredients derived from 7 different plants and asphalt was tested for its adaptogenic activity and its mechanism of action was investigated. DESIGN: CIHP-I was tested using the cold-hypoxia-restraint (C-H-R) animal model in which the restrained rats were exposed to 5 degrees C at 428 mm Hg atmospheric pressure. Rectal temperature (Trec) of the rats was continuously monitored during the exposure and the recovery periods. The time for fall of Trec to 23 degrees C and its recovery to 37 degrees C were used as indices of endurance and the adaptogenic activity. Carbohydrate and lipid parameters were investigated to find out the nature of fuel being used during thermogenesis. RESULTS: After 12 weeks of administration of an oral dose of 7.5 mg/kg(-1)/day(-1), CIHP-I was found to possess significant adaptogenic activity. CIHP-I helped improve resistance to C-H-R induced hypothermia (Trec 23 degrees C) in animals by increased mobilization of free fatty acids (FFA) from adipose tissue. Blood glucose and muscle glycogen levels were maintained. CIHP-I treatment restricted the release of creatine phosphokinase (CPK) into the circulation during C-H-R exposure. CONCLUSIONS: The results suggested that CIHP-I is a strong adaptogen. It improved cold resistance during C-H-R exposure and enhanced recovery from hypothermia. The energy-dependent cell membrane permeability was maintained. Stored lipids were mobilised and possibly used for thermogenesis in preference to carbohydrates.     

Thermoregulation and afterdrop during hypothermia in patients with poikilothermia

The pathophysiology of afterdrop of core temperature duringrewarming in patients with induced or accidental hypothermiaremains controversial. We studied the effect of cooling andrewarming in four female patients with acquired poikilothermiaand in four normal females. Exposure to cold air (16.5°C)induced shivering and adequate vasoconstriction in normal individuals,without a fall in rectal temperature (T_r; 36.3±0.2°C[mean±SD]); subsequent heating (40°C) induced a risein T_rto 37.0±0.3°C and generalized sweating. Thefour patients all had spontaneous hypothermia (T_r 34.1 ±0.9°C) before cooling. T_rdecreased by 0.3-0.9°C duringcold exposure, and a marked after-drop of T_r(0.3–0.5°C)occurred during rewarming: this did not occur in normal individuals.Cooling failed to induce shivering and vasoconstriction in threepatients. No patient showed visible sweating during heatingdespite a T_rof up to 38.0–38.5°C and skin temperatureof up to 37.7–38.5°C. The basal metabolic rate wasdecreased by 71–82% in all patients during steady-statehypothermia and remained lowered during normothermia in twopatients. We conclude that during hypothermia three of the fourpatients showed severe disorders of peripheral vasomotor functionand shivering response. These data provide evidence for thermalconduction as the major mechanism of afterdrop during hypothermia.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Patterns of Insulin Dependence in an African Diabetic Clinic

SUMMARY Analysis of the age of onset of diabetes amongst insulin-treatedpatients in a large African diabetic clinic revealed a bimodaltype of distribution, 23 per cent having an age of onset before30 years and 77 per cent with onset at 30 years of age. All66 of the young insulin-treated group (21.7±4.8 years(mean±1 SD)), and a random selection of 50 older insulin-treatedpatients (49.7±10 years), were studied. The older groupwere better controlled (HbA₁ 8.4±1.7 per cent vs. 10.8±2.6per cent, p<0.001), on lower doses of insulin (49±23vs. 71±23 u/day, p<0.001) and had higher body massindex (26.0±5.6 vs. 21.8±3.5, p<0.001). SerumC-peptide (0.24±0.15 vs. 0.07±0.10 nmol/l, p<0.0001),and C-peptide/glucose ratio (2.57±2.65 vs. 0.56+0.98nmol/mmolx 10², p<0.001) were very significantly higher inolder patients. Patients with later onset disease thus had betterpreservation of pancreatic function, higher body mass indexand better glycaemic control on lower doses of insulin. Thesefeatures suggest that older insulin-treated patients could infact be ‘Type 2’ or non-insulin dependent patients,and the condition may be controllable with diet and/or oralhypoglycaemic agents, at least in some.     

Abnormalities of in vitro Thyroid Function Tests in Renal Disease

In vitro tests of thyroid function, have been performed in 70euthyroid patients with chronic renal disease. Abnormal valueswere observed in 54 out of 87 blood samples (70 per cent). Thecharacteristic pattern was an elevated triiodothyronine (T₃)resin uptake and a subnormal serum total thyroxine (T₄). Theparameters derived from these tests, the free thyroxine index(FTI), and the free thyroxine factor (FTF) also did not alwaysprovide correct diagnostic information, being abnormal in 21per cent and 14 per cent respectively. The ‘free thyroxine’was normal in all except two patients. Thyroxine-binding globulin(TBG) capacity was normal in 67 out of 80 cases (84 per cent).Patients with renal failure did not demonstrate the normal relationshipbetween T₃ resin uptake and free TBG. It is postulated thatthe abnormalities may be due to two factors; firstly, the presencein the serum of an unknown substance displacing thyroxine fromTBG, and secondly, changes in ionic strength altering the bindingproperties of TBG. The thyroid tests returned to normal afterrenal transplantation.     

A comparison of rectal,oesophageal and gastro‐intestinal tract temperatures during moderate‐intensity cycling in temperate and hot conditions

The purpose of this study was to compare three of the most commonly used methods of core temperature (T_core) measurement during cycling under different environmental conditions as there are practical problems associated with each method and, sometimes, uncertainty as to which is the appropriate measure. Eight trained males (O₂max: 60 ± 7 ml kg^?1 min^?1) completed two 60‐min cycling trials at ~70% O₂max at 20°C (MOD) and 35°C (HOT). Measures of T_core were made every 5 min with oesophageal (T_oes) and rectal (T_rec) thermistors and of the gastro‐intestinal tract temperature (T_gi) with a temperature‐sensitive disposable radio pill. During MOD T_oes initially plateaued after 10 min, T_gi after 25 min and T_rec after 50 min, whereas during HOT these times had increased to 25 min for T_oes and 55 min for both T_gi and T_rec. T_oes consistently provided lower readings than T_rec (0·24–0·26°C) and T_gi (0·26–0·28°C) with T_gi and T_rec similar (0·02°C). Readings for T_gi displayed closer agreement with T_rec (ICC = 0·92) than T_oes (ICC = 0·86) with less agreement between T_rec and T_oes (ICC = 0·84). 95% of all T_gi readings were within ±0·5°C of T_rec and within ±0·6°C of T_oes with 95% of all T_oes readings being within ±0·7°C of T_rec. These results demonstrate distinct response times, absolute values and agreement between T_core measured at different body locations under different ambient conditions. Implications and considerations are discussed.     

Intravenous Glucose Tolerance and Mortality in Non-insulin-dependent Diabetes Mellitus

Two hundred and forty-nine patients with non-insulin-dependentdiabetes were entered into a prospective study at diagnosisand examined at presentation and one, three, and five yearslater. Ten years after diagnosis, 34 patients were known tobe dead and 214 alive. A number of factors were significantlyassociated with survival on univariate analysis and appearedto form two independent intra-related groups: a ‘metabolic’group and a ‘degenerative condition’ group. Multivariateanalysis of these two groups showed that glucose tolerance (therate constant K_G for decrease in plasma glucose concentrationafter its intravenous injection) was significantly related tosurvival in the ‘metabolic’ group, and age, bloodpressure and anti-hypertensive therapy were significant in the‘degenerative’ group of factors. A low K_G valuewas more strongly associated with prognosis than any other factor.Values from the one year review were prognostically more usefulthan initial or later values. Indices of insulin secretion weresimilar irrespective of whether patients survived or died, andso we believe the lower K_G values of dead patients were dueto impaired insulin sensitivity. A regression, equation usingthe above factors correctly allocated survival outcome in 81%of subjects.     

Study of Lupus Nephritis in Males

Clinical and pathological findings were studied in 23 male patientswith lupus nephritis who were followed up for a period of 41±36months after renal biopsy. Age at renal biopsy was 31±14years and 19 patients (83 per cent) were between 15 and 50 yearsold. C3 and C4 levels were below normal in 23 (100 per cent)and 16 (70 per cent) respectively, CH₅₀ was <25 u/ml in 67per cent, and antinuclear and anti-DNA antibodies were foundin 87 per cent and 82 per cent respectively. Serum albumin levelincreased from 2.9±0.8 g/dl to 3.7±0.8 g/dl duringthe follow up period (p<0.01), while urinary protein decreasedfrom 2.0±2.3 g/day to 1.4±2.5 g/day. There wasa significant improvement in the degree of haematurai (p <0.01),but serum creatinine levels showed no change (mean 1.5 mg/ml).Active proliferative lupus nephritis of, moderate or severedegree was observed in 65 per cent of patients at the initialbiospsy. A trend to regression in this activity was seen inmost serial biopsies, but the chronicity index showed a slightincrease. These data demonstrate that systemic lupus erythematosusin males, in comparison to our previous report of the diseasein female patients, is accompanied by more active nephritis,but that is follows a benign course with therapy.     

Thrombin and Plasmin Activity in Diabetes Mellitus and their Association with Glycaemic Control

Abnormalities of haemostasis are common in diabetes mellitus.As indicators of fibrinolysis and coagulation, plasmin and thrombinactivity were assessed by assay of the fibrinogen peptide derivativesBß_15-42 and fibrinopeptide A respectively in 60 diabeticpatients and 50 control subjects in a cross-sectional study.Glycosylated haemoglobin (HbA₁) correlated with Bß_15-42(r=0.26, p<0.05) and fibrinopeptide A (r=0.30, p<0.05)in the diabetic patients suggesting that poor glycaemic control(i.e high HbA₁ levels) was associated with depressed plasminand enhanced thrombin activity. Compared to controls, fibrinopeptideA levels were increased in diabetics (p<) irrespective ofsex or type of diabetes. Bß_15-42 levels were normalin diabetic females but increased in diabetic men (p<0.001)possibly secondary to the activation of coagulation. These resultssuggest that in diabetes mellitus activation of coagulationis the dominant haemostatic abnormality and that better glycaemiccontrol could influence in-vivo plasmin and thrombin activityfavourably.     

Parathyroid Acidosis in Uraemia

Acidosis in uraemia is more closely related to the severityof renal bicarbonate wastage than to limitation of ammoniumand titratable acid excretion. Reduction in maximum tubularreabsorptive capacity for bicarbonate (T_MHCO₃) indicates a proximaltubular defect, and was present in all subjects studied. Themagnitude of T_MHCO₃ abnormality appears directly related tothe level of circulating plasma parathyroid hormone (PTH) andto reduction in tubular phosphate reabsorption. The renal acidification defect is similar to that previouslyshown in subjects with hyperparathyroidism of quite differentorigins, due to intestinal malabsorption or to primary (adenomatous)hyperparathyroidism or to simple infusion of parathyroid extractin normal subjects. Elevation of reduced plasma Ca levels by vitamin D in a groupof uraemic subjects was accompanied by a significant rise inplasma bicarbonate but some subjects in whom plasma PTH wasnot suppressed failed to show this response. Surgical parathyroidectomy in two uraemic subjects presentingwith osteitis fibrosa was followed by reversal of systemic acidosiswith restoration of T_MHCO₃.The response was similar to thatpreviously shown following operation in primary (adenomatous)cases. The data give rise to a new emphasis on the importance of bicarbonateloss in the maintenance of uraemic acidosis and provide a rationalexplanation for the stabilization of plasma HCO₃ at levels correspondingto the new low T_M values. Since this type of metabolic acidosis is common to a varietyof clinical conditions associated with high plasma PTH levels,it may conveniently be referred to as ‘parathyroid acidosis’.     

Ozone Therapy for Tumor Oxygenation: a Pilot Study

Tumor hypoxia is an adverse factor for chemotherapy and radiotherapy.Ozone therapy is a non-conventional form of medicine that hasbeen used successfully in the treatment of ischemic disorders.This prospective study was designed to assess the effect ofozone therapy on tumor oxygenation. Eighteen subjects were recruitedfor the study. Systemic ozone therapy was administered by autohemotransfusionon three alternate days over one week. Tumor oxygenation levelswere measured using polarographic needle probes before and afterthe first and the third ozone therapy session. Overall, no statisticallysignificant change was observed in the tumor oxygenation inthe 18 patients. However, a significant decrease was observedin hypoxic values 10 and 5 mmHg of pO₂. When individually assessed,a significant and inverse non-linear correlation was observedbetween increase in oxygenation and the initial tumor pO₂ valuesat each measuring time-point, thus indicating that the morepoorly-oxygenated tumors benefited most (rho = –0.725;P = 0.001). Additionally, the effect of ozone therapy was foundto be lower in patients with higher hemoglobin concentrations(rho = –0.531; P < 0.034). Despite being administeredover a very short period, ozone therapy improved oxygenationin the most hypoxic tumors. Ozone therapy as adjuvant in chemo-radiotherapywarrants further research.     

Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification

We studied the safety and efficacy of milk fortified with vitaminD₃ and calcium. Over the winter, we conducted a double-blind,placebo-controlled trial of fortified milk (12µg vitaminD₃ and 1525 mg calcium per litre) compared to unfortified milk(0.3µg vitamin D₃ and 1270 mg calcium per litre) in 102adults (aged 17–54 years). Serum 25-hydroxyvitamin D [25(OH)D],ionized calcium, and creatinine were measured at baseline andafter intervention. Fortification reduced the seasonal declinein serum 25(OH)D concentrations by >50%. In the fortifiedgroup, serum 25(OH)D decreased by 15nmol/l from 77±35nmol/l to 62±26 nmol/l (p<0.001). In the control group,serum 25(OH)D fell by 31 nmol/l from 85±39 nmol/l to54±25 nmol/l (p<0.001). We suggest that milk enrichedwith vitamin D be provided in high-latitude European countriesto diminish the wintertime fall in serum 25(OH)D.     

ERRATA

In Table III pCO₂ for patient C should readO. In list of references Dolman, P.J., Sullivan, D. W. J.,&Pitts, R. F.(1954) J. clin. Invest. 23, 82 should read33, 82     

Panic Anxiety and Hyperventilation in Patients with Chest Pain: A Controlled Study

We studied the relation between mood disorder and hyperventilation(hypocapnia) before and during exercise treadmill testing in113 chest pain patients attending a cardiac clinic and 30 healthycontrols. In most patients end-tidal P_co2 (P_co2) rose in thenormal way on exercise but in a subset of 24 (21 per cent) therewas no rise: these patients with initial hyperventilation hadsignificantly higher anxiety scores than those with a normalexercise-induced rise in P_CO2. Two of the 24 had ischaemic heartdisease and 10 (42 per cent) complained of recent panic anxietycompared with 12 (13 per cent) of the 89 with normal rise inP_CO2 (p<0.05). Rates of psychiatric morbidity were similar in patients with‘typical’ and ‘atypical’ chest pain.Resting hypocapnia occurred more often in patients with panicanxiety than in either anxious or non-anxious patients withoutpanic. Panic patients also reported more symptoms of breathlessnessand hyperventilation-related complaints than those without panic. Our findings confirm the important association between panicand hyperventilation in patients with chest pain. Furthermore,patients with exercise-induced hyperventilation are more likelyto have a psychiatric than a cardiac disorder. Early detectionand treatment of these patients may reduce the potential morbidityassociated with unnecessary invasive investigations.     

Effect of 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide isolated from the roots of Withania somnifera on stress indices in Wistar rats

OBJECTIVE: Isolation of biologically active fractions and compounds from the roots of Withania somnifera, a plant used extensively as a constituent of rasayana, in Ayurveda and to test their adaptogenic activity on stress indices using the cold-hypoxia-restraint (C-H-R) model. DESIGN: Bioactivity-guided fractionation of an aqueous extract of the roots of Withania somnifera led to the isolation of a new species of withanolide 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide. Structure elucidation, was carried out using proton nuclear magnetic resonance, infrared (IR), ultraviolet (UV), and mass spectroscopic analysis. Stress-related indices were evaluated, namely serum creatine phosphokinase (CPK) activity, serum lactate dehydrogenase (LDH) activity, serum corticosterone levels, and serum lipid peroxidation (LPO) levels. RESULTS: There was a significant decrease in a serum CPK, LDH, and LPO levels in animals pretreated with (1) fraction-I (20 mg/kg body weight), (2) 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (2.5 mg/kg body weight) in comparison to control when subjected to C-H-R stress. CONCLUSIONS: The results show that the a new species of withanolide, 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (compound-1) could prove to be an effective agent to counteract C-H-R stress.     

Neuroprotection by Brazilian Green Propolis against In vitro and In vivo Ischemic Neuronal Damage

We examined whether Brazilian green propolis, a widely usedfolk medicine, has a neuroprotective function in vitro and/orin vivo. In vitro, propolis significantly inhibited neurotoxicityinduced in neuronally differentiated PC12 cell cultures by either24 h hydrogen peroxide (H₂O₂) exposure or 48 h serum deprivation.Regarding the possible underlying mechanism, propolis protectedagainst oxidative stress (lipid peroxidation) in mouse forebrainhomogenates and scavenged free radicals [induced by diphenyl-p-picrylhydrazyl(DPPH). In mice in vivo, propolis [30 or 100 mg/kg; intraperitoneallyadministered four times (at 2 days, 1 day and 60 min before,and at 4 h after induction of focal cerebral ischemia by permanentmiddle cerebral artery occlusion)] reduced brain infarctionat 24 h after the occlusion. Thus, a propolis-induced inhibitionof oxidative stress may be partly responsible for its neuroprotectivefunction against in vitro cell death and in vivo focal cerebralischemia.