Chronic oral administration of raw garlic protects against isoproterenol-induced myocardial necrosis in rat

Wistar albino rats (150-200 g) were fed raw garlic homogenate orally in three different doses (125, 250, 500 mg/kg/day) for 30 days. Isoproterenol (85 mg/kg, s.c. 2 doses at 24-h interval, animals sacrificed after 24 h of last injection) induced myocardial necrosis in control rats and after 30 days of garlic feeding. Myocardial oxidative stress was evident following isoproterenol administration by reduction in myocardial superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities along with a rise in plasma thiobarbituric acid reactive substances (TBARS). Myocardial necrosis was evident from the light microscopic and ultrastructural changes, along with a rise in plasma lactate dehydrogenase (LDH). Significant preservation of myocardial SOD activity was observed in all the garlic-fed rats. However, there was no significant change in myocardial reduced glutathione level and GPx activity in any of the treated groups. Significant reduction in plasma TBARS and LDH levels was observed in the 500 mg/kg garlic treated group. Isoproterenol-induced myocardial morphological changes were least in the 250 and 500 mg/kg garlic treated groups. The results suggest that chronic oral administration of raw garlic offered protection against isoproterenol-induced myocardial necrosis and associated oxidative stress.     

Modulation of PPAR-γ by telmisartan protects the heart against myocardial infarction in experimental diabetes

Telmisartan, an angiotensin II-receptor blocker (ARB), is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-γ). We investigated whether telmisartan improved the pathophysiology of myocardial infarction in diabetes partially through the PPAR-γ pathway by assessing a variety of indices, e.g., hemodynamic, biochemical, histoarchitectural changes, and apoptosis. Diabetes was induced by a single dose of streptozotocin (70 mg/kg, IP). Diabetic rats received either telmisartan (10 mg/kg/day, orally), the PPAR-γ antagonist GW9662 (1 mg/kg/day, IP), or both for 14 days with concurrent administration of isoproterenol (85 mg/kg, SC) on days 13 and 14. Compared with diabetic controls, diabetic rats with myocardial infarction exhibited altered hemodynamic profiles and reduction in the activities of creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level along with increased level of malondialdehyde in the heart. Further, diabetic animals with myocardial infarction exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with telmisartan significantly improved the redox status of the myocardium with subsequent cardiac functional recovery. However, significant effects were lowered in animals treated with telmisartan plus GW9662. Telmisartan markedly inhibited Bax expression, TUNEL-positive cells, myonecrosis, and edema. On the other hand, administration of telmisartan plus GW9662 did not elicit the same effects, nor did they increase Bcl-2 protein expression in isoproterenol-induced myocardially infarcted diabetic rats when administered concomitantly or individually. Moreover, down-regulated PPAR-γ expression in myocardially infarcted diabetic hearts was increased by telmisartan treatment. In addition to class effects of ARBs, telmisartan reduces oxidative stress and apoptosis and improves cardiac function via the PPAR-γ pathway.     

Caffeine-phenylethylamine combinations mimic the amphetamine discriminative cue

Although caffeine-phenylethylamine combinations are widely available as over-the-counter medications or as "legal" stimulants, little information is available concerning their behavioral pharmacology or abuse potential. In the present study, rats were trained in a food-reward, two-lever operant drug discrimination paradigm to differentially respond after saline or 0.5 mg/kg amphetamine injections. Tests for generalization to the amphetamine cue indicated only modest amphetamine-lever responding at various doses of caffeine alone or at various doses of ephedrine/phenylpropanolamine (PPA) combinations, but complete generalization to the training cue was found with higher doses of the triple combination (caffeine, ephedrine, and PPA) or with caffeine-ephedrine or caffeine-PPA combinations. All drugs produced response rate decreases at higher doses. These data clearly indicate that certain "legal" stimulants mimic the amphetamine cue and suggest that caffeine may interact additively with phenylethylamines to produce the cue.     

Changes in angiotensin receptors expression play a pivotal role in the renal damage observed in spontaneously hypertensive rats

The renal renin-angiotensin system plays a central role in the development of hypertension. The aim of this work was to verify the expression of angiotensin II receptors AT(1)R and AT(2)R in the microsomal fraction of renal cortex and correlate this with the development of hypertension and renal damage in spontaneously hypertensive rats (SHR) using Wistar-Kyoto rats (WKY) as controls. AT(1)R expression increased (126%) and AT(2)R expression decreased (66%) in 4-wk-old SHR; AT(2) expression decreased in 14-wk-old SHR (61%) compared with respective age-matched WKY. These modifications were correlated to the increase in protein kinase C activity and decrease in protein kinase A activity. Four-week-old SHR showed large accumulations of macrophages in kidney glomerulus and the tubulointerstitial area, dense cortical collagen deposition, and arterial proliferative changes in the walls of arterioles and medium-sized vessels. Similar modifications were also observed in 14-wk-old SHR. Four-week-old SHR treated with losartan (30 mg·kg(-1)·day(-1)) or hydralazine (15 and 30 mg·kg(-1)·day(-1)) by gavage for 10 wk did not develop hypertension. The decrease in AT(2)R expression and renal damage observed in SHR remained even after treatment with hydralazine. On the other hand, losartan treatment prevented the modifications observed in 14-wk-old SHR, indicating that renal injuries are caused specifically by AT(1) rather than an increase in blood pressure. Our results indicate that the imbalance in AT(1)R and AT(2)R expression is associated with an inflammatory process that contributes to renal injury in adult SHR and to the development of hypertension.     

Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat

Angiotensin II contributes to myocardial tissue remodeling and interstitial fibrosis through NADPH oxidase-mediated generation of oxidative stress in the progression of heart failure. Recent data have suggested that nebivolol, a third-generation β-blocker, improves diastolic dysfunction by targeting nitric oxide (NO) and metabolic pathways that decrease interstitial fibrosis. We sought to determine if targeting NO would improve diastolic function in a model of tissue renin-angiotensin system overactivation. We used the transgenic (TG) (mRen2)27 rat, which overexpresses the murine renin transgene and manifests insulin resistance and left ventricular dysfunction. We treated 6- to 7-wk-old TG (mRen2)27 rats and age-matched Sprague-Dawley control rats with nebivolol (10 mg·kg(-1)·day(-1)) or placebo via osmotic minipumps for a period of 21 days. Compared with Sprague-Dawley control rats, TG (mRen2)27 rats displayed a prolonged diastolic relaxation time and reduced initial filling rate associated with increased interstitial fibrosis and left ventricular hypertrophy. These findings were temporally related to increased NADPH oxidase activity and subunits p47(phox) and Rac1 and increased total ROS and peroxynitrite formation in parallel with reductions in the antioxidant heme oxygenase as well as the phosphorylation/activation of endothelial NO synthase and PKB/Akt. Treatment with nebivolol restored diastolic function and interstitial fibrosis through increases in the phosphorylation of 5'-AMP-activated protein kinase, Akt, and endothelial NO synthase and reductions in oxidant stress. These results support that targeting NO with nebivolol treatment improves diastolic dysfunction through reducing myocardial oxidative stress by enhancing 5'-AMP-activated protein kinase and Akt activation of NO biosynthesis.     

The influence of intracerebroventricular administration of (+/-) propranolol and (+/-) verapamil on experimental myocardial ischemia and necrosis in rats

In albino rats, infarctoid myocardial lesions were produced by intraperitoneal (i.p.) administration of isoproterenol (75 mg/kg, during 3 days). In other groups, the descending anterior left coronary artery was ligated. In both experimental settings, the intracerebroventricular (i.c.v.) administration of (+/-) propranolol (100-200-300 microg/animal/day, during 7 days) or (+/-) verapamil (40-80-160 microg/animal/day, during 7 days) afforded a significant protection (with the exception of the lowest dose) on the investigated parameters: arrhythmias, ischemic zone (in coronary ligated rats), lactate dehydrogenase and aspartate aminotransferase activity of the serum, focal necrosis (in isoproterenol treated rats). This protective activity is lower than that afforded by i.p. administered (+/-) propranolol (5 mg/kg, during seven days) or (+/-) verapamil (5 mg/kg, during seven days). From these data it may be concluded that (+/-) propranolol and (+/-) verapamil have a protective action on the experimental myocardial ischemia and necrosis in rats, not only when the drugs come in direct contact with the heart, but also acting upon the central nervous system.     

Caffeine effects on the chromosomal aberrations induced in vivo by sarcolysine and methotrexate

Wistar adult rats bearing Guérin T8 ascite tumours were intravenously inoculated with 3 mg/kg b.w. sarcolysine and respectively 5 mg/kg b.w. methotrexate on the 7th day after ascite cells grafting. Four hours after cytostatic administration, 5 mg/kg b.w. caffeine was intravenously given. Cytogenetic observations concerning the frequency and the type of induced chromosomal aberrations were performed 24 hrs after cytostatic administration, both in the animals treated with only sarcolysine, methotrexate and caffeine and in those double-treated with cytostatics and caffeine. Chromosome examinations were also performed in untreated controls. Both in the sarcolysine- and methotrexate- treated tumors, the induced chromosome lesions were enhanced by caffeine administration, but this effect was very obvious in the methotrexate experiments and rather weak in the sarcolysine treatments (see table). This different effect of caffeine might be due to the different mechanisms by which sarcolysine and methotrexate are interfering in DNA replicating processes.     

The Effects of Caffeine on <Emphasis Type="SmallCaps">l</Emphasis>-Arginine Metabolism in the Brain of Rats

In our study, the short-term effects of caffeine on L- arginine metabolism in the brains of rats were investigated. Caffeine was given orally at two different doses: 30 mg/kg and 100 mg/kg (a high non-toxic dose). Brain tissue arginase activity in rats from the caffeine-treated groups decreased significantly compared with the control group. Malondialdehyde (MDA) levels in the brain tissue and serum of animals in the caffeine groups also decreased significantly. Brain tissue and serum nitric oxide (NO) levels increased significantly after caffeine administration. Tumor necrosis factor-α (TNF-α) levels were also investigated in rat serum, but there was no statistically significant difference between the TNF-α levels of the caffeine-treated rats groups and the control rats. Our study indicates that brain arginase activity decreases after caffeine administration at doses of 30 mg/kg and 100 mg/kg. As a result, we can say that arginine induces production of NO in the organism.     

Effects of chronic administration of doxorubicin on myocardial beta-adrenergic receptors

The effects of multiple doses of doxorubicin (DXR) on myocardial beta-adrenergic receptor density and dissociation constant were investigated in male Sprague Dawley rats. The rats received DXR (2 mg/kg) or vehicle weekly by the SC route for 13 weeks. One group of DXR-treated rats plus corresponding controls were sacrificed at 14 weeks, one week after the last dose. Another group of DXR-treated rats plus corresponding controls were sacrificed at 19 weeks, six weeks after the last dose. The myocardial beta-adrenergic receptor was characterized by radio-ligand binding studies using [125I]iodocyanopindolol. Beta--receptor densities in DXR-treated rats of 7.0 and 7.4 fm/mg protein were unchanged from control levels of 7.2 fm/mg protein at both 14 and 19 weeks, respectively. Receptor dissociation constants in DXR-treated rats of 36.7 and 36.9 pM were increased over control levels of 24.6 and 30.0 pM at 14 and 19 weeks, respectively. However, the change in dissociation constant is only significant at 14 weeks. The increased dissociation constants suggest diminished agonist binding affinity of the myocardial beta-receptor. This impaired response of the receptor to catecholamines would tend to diminish the ability of myocardium to adequately respond to adrenergic stimuli.     

Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice

Chronic administration of caffeine to mice (1 mg/ml in drinking water X 14 d) led to a downward shift in the dose-response curve for the locomotor effects of caffeine. Caffeine was also less effective as an antagonist against (-)-(N6-phenylisopropyl)-adenosine (PIA)-induced analgesia in the tail flick assay in these animals. The dose-response curves of PIA for both analgesia and locomotor depression were shifted to the left in animals chronically administered caffeine. In mice chronically administered PIA (1 mg/kg/d X 14 d), the dose-response curves of PIA for both analgesia and locomotor depression were shifted to the right. The dose-response curve for the locomotor effects of caffeine was shifted to the left, and caffeine exhibited greater antagonist activity against the analgesic action of PIA in these animals. There was no change in the Kd or Bmax values of either 3H-PIA or 3H-diethylphenylxanthine (DPX, a potent adenosine receptor antagonist) in mice chronically administered PIA. The Bmax values for both 3H-PIA and 3H-DPX were significantly increased, while the Kd values were not changed in mice chronically administered caffeine. There was no detectable change in the brain levels of either PIA or caffeine in animals chronically treated with either drug. The results demonstrate that chronic administration of caffeine increases the sensitivity of mice to the actions of PIA and vice versa, providing supportive evidence for the interaction of these drugs at the same receptor, which is probably an adenosine receptor.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Effects of chronic caffeine ingestion on growth and myocardial function

Experiments were conducted to determine whether chronic caffeine consumption during early growth and development affected cardiac performance and development of adipose tissue. Dams were fed a nutritionally complete diet with or without the addition of 10 mg/kg caffeine during lactation. After weaning, the pups were maintained on this diet until they were sacrificed at 88 days of age. Body weight at the time of sacrifice was comparable for both groups. The hearts from caffeine-fed animals were significantly (P less than 0.05) larger based on both dry and wet weights although the dry weight/wet weight ratios were similar. Ventricular function curves were generated on each heart using an isolated working heart preparation. The isolated hearts of caffeine-fed rats exhibited a significant reduction in cardiac output, stroke volume, mean aortic pressure, and estimated myocardial work when compared to controls. The rats fed caffeine had greater plasma triglyceride levels with no significant differences in adipocyte size or number in the epididymal and perirenal depots. It is concluded that chronic caffeine intake from birth may alter cardiac function of the offspring.     

Death in ventricular fibrillation induced by isoproterenol in DOCA-salt pretreated rats preceded by changes in myocardial electrolytes

Serum and tissue content of sodium, potassium, magnesium and calcium was determined in controls and desoxycorticosterone acetate (DOCA)-salt treated rats to determine whether electrolyte changes preceded the development of isoproterenol-induced death in ventricular fibrillation. Control Sprague Dawley, male rats, were injected subcutaneously (s.c.) with either saline (Group A) or actinomycin D (0.1 mg/kg; Group B) once daily for 4 days. Other rats received 20 mg of DOCA by implantation, drank normal saline and were injected with either saline (Group C) or actinomycin D (Group D) once daily for 4 days. In the first part of the experiment, it was determined that none of 15 rats from Group C died when challenged with isoproterenol (150 micrograms/kg, s.c.) six days later: however, 13 out of 15 rats from Group D died within 29.1 +/- 15.0 minutes (mean +/- S.D.) from isoproterenol injection. Myocardial sodium was elevated (48.8 +/- 3.8 versus 36.3 +/- 1.9) and potassium decreased (60.4 +/- 3.4 versus 70.6 +/- 3.3, meq/kg wet weight, mean +/- S.D.) in rats that had succumbed to isoproterenol. In the second part of the experiment serum and tissues were removed from control and DOCA-saline pretreated rats before they died in ventricular fibrillation, 20 minutes after isoproterenol. DOCA-saline pretreated rats were hypernatremic and hypokalemic and exhibited higher sodium and lower potassium in skeletal muscle than control rats. Isoproterenol elicited hypokalemia in all rats, but it only elevated sodium and decreased potassium content in the myocardium of rats of Group D, that were more prone to die in ventricular fibrillation. It is concluded that myocardial electrolyte changes precede the onset of ventricular fibrillation and may be associated with the development of this dysrhythmia.     

Treatment of Hypothalamic Obesity with Caffeine and Ephedrine

ObjectiveTo investigate the hypothesis that the peripheral actions of caffeine and ephedrine to increase sympathetic tone and metabolic rate and to preserve lean tissue will cause weight loss in patients with hypothalamic obesity.MethodsWe present 3 case studies of consecutive patients who presented with hypothalamic obesity and were treated with caffeine (200 mg) and ephedrine hydrochloride (25 mg) 3 times a day.ResultsAll patients were gaining weight at the time of initial assessment. The first patient lost 8% to 9% of her body weight and maintained that loss for the subsequent 2 years. The second patient lost 18.8% of her body weight and was maintaining a 9.5% weight loss after 6 years. The third patient lost 14% of her body weight during a 6- month period and gradually returned to her baseline weight during a period of 5 years, after which she was referred for bariatric surgical treatment.ConclusionThese 3 patients with hypothalamic obesity, who had been steadily gaining weight, lost a mean of 13.9% of their body weight, and 2 of them maintained weight loss for a period of years. Thus, caffeine and ephedrine appeared to halt weight gain and maintain a clinically significant weight loss in 2 of our 3 patients. A randomized clinical trial to confirm these findings would be appropriate but difficult because of the rarity of this disorder. (Endocr Pract. 2008;14:697-703)     

Thermoregulatory effects of purines and caffeine

Purines are putative neurotransmitters which appear to be involved in regulating several vegetative functions. We examined the effect of purines and their antagonist, caffeine, on colonic temperature of rats. Adenosine injected ip lowered colonic temperature in a dose responsive manner at ambient room temperatures. Adenine and AMP also lowered body temperature whereas 7-methylinosine and inosine only slightly influenced colonic temperature. Caffeine (50 mg/kg) injected sc, increased colonic temperature and when injected within 60 seconds of adenosine, counteracted the hypothermic effect of adenosine (50 mg/kg). Low ambient temperature (4°C) accentuated the thermoregulatory effects of adenosine. Thus adenosine appears to have a hypothermic effect on body temperature regulation when administered peripherally which can be reversed by caffeine.     

Effect of caffeine-coconut products interactions on induction of microsomal drug-metabolizing enzymes in Wistar Albino rats.

Effect of caffeine-coconut products interactions on induction of drug-metabolizing enzyme in wistar albino rats was studied. Twenty rats were randomly divided into four groups: The control group (1) received via oral route a placebo (4.0ml of distilled water). Groups 2 to 4 were treated for a 14-day period with 50 mg/kg body weight of caffeine, 50 mg/kg body weight of caffeine and 50 mg/kg body weight of coconut water, and 50 mg/kg body weight of caffeine and 50 mg/kg body weight of coconut milk in 4.0ml of the vehicle via gastric intubation respectively. One day after the final exposure, the animals were anaestheticized by inhalation of an overdose of chloroform. The blood of each rat was collected by cardiac puncture while the liver of each rat was harvested and processed to examine several biochemical parameters, i.e., total protein and RNA levels, protein/RNA ratios, and activities of alanine and aspartate amino transferase (ALT and AST, respectively). The results showed that while ingestion of coconut milk and coconut water increased the values of protein and protein/RNA ratios, it decreased alanine and aspartate amino transferase (ALT and AST) activities. These effects, in turn, enhanced the induction of the metabolizing enzymes and a resultant faster clearance and elimination of the caffeine from the body, there by reducing the toxic effect on the liver.     

Effects of caffeine on blood pressure, heart rate, and forearm blood flow during dynamic leg exercise

This study examined the acute effects of caffeine on thecardiovascular system during dynamic leg exercise. Ten trained,caffeine-naive cyclists (7 women and 3 men) were studied at rest andduring bicycle ergometry before and after the ingestion of 6 mg/kgcaffeine or 6 mg/kg fructose (placebo) with 250 ml of water. Afterconsumption of caffeine or placebo, subjects either rested for 100 min(rest protocol) or rested for 45 min followed by 55 min of cycleergometry at 65% of maximal oxygen consumption (exercise protocol).Measurement of mean arterial pressure (MAP), forearm blood flow (FBF),heart rate, skin temperature, and rectal temperature and calculation offorearm vascular conductance (FVC) were made at baseline and at 20-minintervals. Plasma ANG II was measured at baseline and at 60 minpostingestion in the two exercise protocols. Before exercise, caffeineincreased both systolic blood pressure (17%) and MAP (11%) withoutaffecting FBF or FVC. During dynamic exercise, caffeine attenuated theincrease in FBF (53%) and FVC (50%) and accentuated exercise-inducedincreases in ANG II (44%). Systolic blood pressure and MAP were alsohigher during exercise plus caffeine; however, these increases weresecondary to the effects of caffeine on resting bloodpressure. No significant differences were observed inheart rate, skin temperature, or rectal temperature. These findingsindicate that caffeine can alter the cardiovascular response to dynamicexercise in a manner that may modify regional blood flow andconductance.

     

Biochemical and histologic presentations of female wistar rats administered with different doses of paracetamol/methionine

This study was carried out to compare the hepatoprotective effect of methionine on paracetamol treated rats at both the peaks of toxicity and absorption. Female Wistar rats were divided into 17 groups consisting of eight rats per group and treated with different doses of paracetamol/methionine (5:1). Each control rat received 5 ml of physiologic saline. The study was terminated at two different end points -the 4th and 16th hours. Results show that rats administered with toxic doses (1000 mg/kg, 3000 mg/kg, 5000 mg/kg BW) of paracetamol exhibited significant increases in the levels of ALT, AST, γ- GT compared with controls. These increases were much higher at the 16th than 4th hour but serum total protein, albumin and globulin were significantly decreased by the end of the 16th hour. Histology results of rats in the 3000 and 5000 mg/kg (by the end of the 16th hour) confirmed hepatic damage, light microscopic evaluation of liver showed remarkable centrilobular necrosis. Moreover, the presence of mononuclear cells in liver section of rats intoxicated with APAP (5000 mg/kg) suggests a possible involvement of inflammatory process which resulted in regurgitation of bilirubin leading to its elevated level as well as increase activity of ALP. The hepatoprotective effect of methionine, on the other hand, was demonstrated in these rats at the 4th and 16th hours, and both results were comparable and therefore not significantly different but elevation in GGT level still persisted. In conclusion, data obtained from this study suggest that these agents may be capable of inducing GGT, although further study is required to establish a possible relationship between methionine and this enzyme in some other animal species.     

24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: Implications for caffeine-induced depression

Caffeine injected at doses of 20, 40 and 80 mg/kg increased brain levels of tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in rat brain. In view of a possible role of 5-HT in caffeine-induced depression the effects of repeated administration of high doses of caffeine on brain 5-HT metabolism are investigated in rats. Caffeine was injected at doses of 80 mg/kg daily for five days. Control animals were injected with sahne daily for five days. On the 6th day caffeine (80 mg/kg) injected to 5 day sahne injected rats increased brain levels of tryptophan, 5-HT and 5-HIAA. Plasma total tryptophan levels were not affected and free tryptophan increased. Brain levels of 5-HT and 5-HIAA but not tryptophan decreased in 5 day caffeine injected rats injected with sahne on the 6th day. Plasma total and free tryptophan were not altered hi these rats. Caffeine-induced increases of brain tryptophan but not 5-HT and 5-HIAA were greater in 5 day caffeine than 5 day sahne injected rats. The findings are discussed as repeated caffeine administration producing adaptive changes in the serotonergic neurons to decrease the conversion of tryptophan to 5-HT and this may precipitate depression particularly in conditions of caffeine withdrawal.     

Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life

Seizures early in life cause long‐term behavioral modifications, namely long‐term memory deficits in experimental animals. Since caffeine and adenosine A_2A receptor (A_2AR) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long‐term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7‐days‐old (P7) rats caused a single period of self‐extinguishable convulsions which lead to a poorer memory performance in the Y‐maze only when rats were older than 90 days, without modification of locomotion or anxiety‐like behavior in the elevated‐plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP‐25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD‐95, NMDA receptor subunits (NR1, NR2A, NR2B) or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A_2AR antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A_2AR antagonists.