Biomedical subjects
Publications and source records attributed to M Beni.
A hypertensive diabetic woman, who was resistant to any pharmacological therapy, underwent to check for secondary hypertension. The treatment with the particularly active ACE inhibitor quinapril failed but it suggested a procedure for a fast differential diagnosis of disease.
The changes induced by nerve growth factor (NGF) and by GM1-ganglioside administration on serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan content and on choline acetyltransferase activity, were studied in the central nervous system of rats undergoing electrolytic damage of a mesencephalic area, located near the nucleus interpeduncularis. This lesion selectively reduced the content of 5-HT and 5-HIAA in the ipsilateral hippocampus. Daily intraperitoneal injection of GM1-ganglioside (30 mg/kg/day for 6-14 days) significantly reduced the injury-induced loss of hippocampal 5-HT and 5-HIAA content. On the contrary NGF, administered at a dose (10 micrograms/rat i.c.v. twice a week for 2 weeks) which was able to increase, in the same animals, the cortical choline acetyltransferase activity, failed to affect the lesion-induced reduction of 5-HT and of 5-HIAA in the hippocampus.
The effects of acute or repeated hydrocortisone administration were studied on the content of quinolinic acid (QUIN), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) assessed by mass fragmentography (QUIN) and high-performance liquid chromatography (5-HT and 5-HIAA) in various brain areas of the rat. Acute administration of the steroid did not significantly modify the brain content of these tryptophan metabolites while, when repeatedly administered at doses of 5 or 50 mg/kg i.p., hydrocortisone significantly reduced the cortical content of QUIN (by 28%, P less than 0.05 and 21%, P less than 0.05 respectively) and the utilization of 5-HT (as evaluated from the ratio 5-HIAA/5-HT by 22%, P less than 0.05 at 50 mg/kg). These data confirm that hydrocortisone administration affects tryptophan metabolism in the rat.
Kynurenic acid, a biologically active tryptophan metabolite, has been identified and measured in the rat brain and other organs using HPLC and GC/MS. Both the described methods required extraction of the compound in alkaline ethanol and initial purification on Dowex ion-exchange resins. The GC/MS approach used 3-hydroxy-2-naphthoic acid as an internal standard and a derivatization procedure with diazomethane and trifluoroacetic anhydride. The HPLC procedure was performed on a reverse-phase column using a spectrophotometric detector. Both the GC/MS and the HPLC methods had the lowest detection limit in the range of 10 pmol/injection, but the variability of the results was lower when HPLC was used. HPLC analysis showed the content of kynurenic acid to be 14 +/- 2 pmol/g wet wt in the brain, 75 +/- 7 in the heart, 87 +/- 8 in the liver, and 298 +/- 10 in the kidneys. Comparable but variable values were obtained with GC/MS.
The effects of administration of GM1 ganglioside on the content of 5-HT and of 5-HIAA in the hippocampus after two different types of lesions of the serotoninergic afferents to the hippocampus were studied. The first type of lesion consisted in severing the dorsal hippocampal afferents. This caused a monolateral decrease of the content of 5-HT and of 5-HIAA in the hippocampal by 60 and 38%, respectively. Since a partial spontaneous recovery occurred after 40-60 days, this model has been used in the past to study sprouting phenomena in the 5-HT system. Daily intraperitoneal administration of GM1 ganglioside (30 mg/kg), for up to 60 days, did not modify this partial recovery. The second lesion consisted of electrolytic damage to a mesencephalic area, where scattered 5-HT cells projecting to the hippocampus are known to be located. The content of 5-HT and 5-HIAA in the hippocampus, ipsilateral to this lesion, decreased by 37 and by 26%, respectively. Administration of GM1 ganglioside (30 mg/kg/day for 6-14 days) partially antagonized the decrease of both 5-HT and 5-HIAA induced by the lesion. These data are in agreement with the view that gangliosides may reduce neuronal injury after mechanical lesions, with a mechanism which is probably not related to neuronal sprouting.
Kynurenic acid, a tryptophan metabolite able to antagonize the actions of the excitatory amino acids, has been identified and measured for the first time in the brain of mice, rats, guinea pigs, and humans by using an HPLC method. Its content was 5.8 +/- 0.9 in mouse brain, 17.8 +/- 2.0 in rat brain, 16.2 +/- 1.5 in guinea pig brain, 26.8 +/- 2.9 in rabbit brain, and 150 +/- 30 in human cortex (pmol/g wet wt. mean +/- SE). The regional distribution of this molecule was uneven. In rats, guinea pigs, and rabbits, the brainstem was the area richest in this compound. Tryptophan administration (100-300 mg/kg, i.p.) to rats resulted in a significant increase of the brain content of kynurenic acid. Similarly, 1 h after probenecid administration (200 mg/kg, i.p.), the brain content of kynurenate increased by fourfold, thus suggesting that its turnover rate is relatively fast.
By use of a simple anticonflict procedure (Vogel test), it was demonstrated that L-pyroglutamic acid (L-pyrrolidone carboxylic acid [L-PCA]), an amino acid naturally occurring in mammalian tissues and fluids, possesses anxiolytic activity. This tissues and fluids, possesses anxiolytic activity. This effect was stereospecific (D-PCA was inactive) and, in the rat, it was not associated with a decrease in motor activity. Ro 15-1788, a benzodiazepine antagonist, did not modify L-PCA actions. Furthermore, anxiolytic doses of the amino acid did not change the content of 5-hydroxytryptamine (5-HT) or of 5-hydroxyindoleacetic acid (5-HIAA) in the rat cortex and hippocampus. These results suggest that the mechanism of the anxiolytic activity of L-PCA is different from that of the benzodiazepines and of 5-HT1a agonists.
The time course of the changes of the hippocampal 5-hydroxytryptamine (5-HT) system after a lesion of the dorsal afferents to this brain area was studied by measuring the content of 5-HT and of 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal, medial and ventral hippocampus. Furthermore, the binding sites for [3H]5-HT, [3H]ketanserin, [3H]imipramine and [3H]mianserin and a 5-HT-mediated behavior (head-twitch responses) were studied in controls and in animals bearing such a lesion. The contents of 5-HT and of 5-HIAA are higher in the ventral than in the dorsal hippocampus. Seven days after the lesion the 5-HT content decreases by 78% in the dorsal and by 50% in the ventral hippocampus. However, 60 days later, a partial recovery, possibly due to a collateral sprouting, does occur. The ratios between 5-HIAA and 5-HT are also increased 10, 14 and 21 days after the lesion, suggesting an increased utilization of the amine by the remaining neuronal terminals. The Bmax of the recognition sites for [3H]5-HT and [3H]mianserin, but not those for [3H]ketanserin are increased 10 days after the lesion and this increase lasts at least 30 days. Finally, starting 10 days after surgery and lasting for 40 days, a 5-HT-mediated behavior (head-twitch responses) shows supersensitivity. These results suggest that important changes occur in the 5-HT innervation of the hippocampus after a mechanical lesion: among these we showed a slow collateral sprouting, an increased utilization of the amine and a supersensitivity of 5-HT receptors.
The effects of acute or repeated administration of indole-pyruvic acid (IPA), a keto-analogue of tryptophan (TRP), were studied in various brain areas of rats by measuring the changes of 5-hydroxytryptamine (5-HT) and of norepinephrine (NE) content and metabolism. The analgesic and sedative properties of the molecule were evaluated by measuring the tail-flick latency, the spontaneous activity and the potentiation of the barbiturate-induced sleep. Acute or repeated administrations of IPA (20 or 50 mg/kg) increased the utilization of 5-HT in the cortex, hippocampus, diencephalon and brain-stem of rats fed a standard laboratory diet. IPA, however, did not substitute TRP in rats fed a TRP-free diet. The administration of this keto-analogue resulted also in a decreased content of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the cortex and in the brain-stem, thus suggesting a decreased utilization of NE in these areas. Furthermore, IPA administration decreased the rats' spontaneous activity, increased the duration of barbiturate-induced sleep and increased the tail-flick time, thus indicating that it has sedative and analgesic properties.