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The effect of methylazoxymethanol (MAM), administered on the 15th gestational day, on the density and pattern of muscarinic cholinergic receptors in some brain areas was assessed using combined radioreceptor binding and autoradiographic techniques. The effect of 15 days' treatment with acetyl-L-carnitine on the same parameter was also assessed. The density of muscarinic cholinergic receptors was found to be increased in the brain of MAM-microencephalic rats. Acetyl-L-carnitine administration caused a significant reduction in the density of receptors under study. A possible role of acetyl-L-carnitine in restoring central cholinergic neurotransmission is discussed.

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The effects of methylazoxymethanol acetate (MAM) administered on the 15th gestational day, and of acetyl-L-carnitine treatment, on rat brain total and ribosomal RNA levels, were studied. In the brain of MAM-treated rats both total and ribosomal RNA concentrations were significantly reduced. Acetyl-L-carnitine treatment restored total and ribosomal RNA levels. The frontal cortex and the hippocampus were the brain areas most sensitive to acetyl-L-carnitine administration. Histochemical demonstration of tissue stores of nucleic acids showed that the loss of RNA induced by MAM occurs primarily within the cytoplasm of nerve cells in various telencephalic areas. Neuronal cytoplasmatic RNA is also sensitive to acetyl-L-carnitine treatment.

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The ageing rat hippocampus undergoes ultrastructural changes, including the loss of axosomatic synapses of the granule cells. These synapses are supposed to take part in a feed-back regulation of granule cell activity, as they are inhibitory terminals of interneurons which receive afferences from the granules themselves via the giant synapses formed by the collaterals of the mossy fibres. In the present study the authors performed a quantitative analysis of axosomatic and giant synapses at the ultrastructural level in aged rats as compared with young animals. In aged rats a decrease both in axosomatic synapses and in giant synapsis vesicles was found, giving further support to the postulated feed-back mechanism. Both young and old rats were treated with L-acetyl-carnitine, a drug which favours the synthesis of acetylcholine, the main neurotransmitter deficient in old age. In aged rats the drug restored a normal number of both axosomatic synapses and giant bouton vesicles. The authors hypothesize that the drug, by a cholinergic-type mechanism, restores the excitatory afferences to the granule whose axon would thus form normal giant boutons with the interneuron, reestablishing the feed-back regulation. In young rats the drug induced a decrease only of the axosomatic synapses, suggesting that an "over-excitation" might impair the information to the local-circuit neurons, thus interrupting feed-back control.

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The effect of methylazoxymethanol (MAM) administration at the 15th gestational day on some behavioural and morpho-functional parameters of rat brain was investigated. The effect of a 13-15-day treatment of acetyl-L-carnitine on the same parameters was also assessed. MAM microencephalic rats showed a significant impairment in water-maze and pole-climbing tests. The histochemical reactivity of the enzyme NADH2-tetrazolium reductase (NADHR) at the level of frontal and occipital cortex, neostriatum and hippocampus was remarkably reduced. Also cholinacetyltransferase (ChAT) immunoreactivity within nerve cell bodies of the pontine tegmentum was decreased in MAM-treated animals. On the contrary, acetylcholinesterase (AChE) reactivity was increased in all the investigated brain areas with the sole exception of the neostriatum. Nissl reactivity was decreased in the cytoplasm of the pyramidal neurons of the frontal cortex and hippocampus, and slightly increased in the cytoplasm of pyramidal neurons of the occipital cortex of MAM microencephalic rats. Acetyl-L-carnitine treatment improved the behaviour of microencephalic rats in water-maze and pole-climbing tests. Moreover the substance stimulated NADHR reactivity in the cerebral cortex and hippocampus as well as ChAT immunoreactivity in the cytoplasm of neurons of the raphe pontine nuclei. Pharmacological treatment reduced AChE reactivity in the cerebral cortex and the hippocampus, and improved the pattern of Nissl reactivity within all brain areas examined.

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The aim of the study was to evaluate the effects of acetyl-L-carnitine on learning and/or memory processes in laboratory animals. In the water maze test, acetyl-L-carnitine, given intraperitoneally at doses ranging from 0.3 to 100 mg/kg, improved performances in both mice and rats. In the latter the drug also proved active when administered orally in the 3-100 mg/kg dosage range. In the pole climbing test in the rat, acetyl-L-carnitine at doses ranging from 0.03 to 10 mg/kg i.p. increased the conditioned reflex learning rate. In the passive avoidance test in the rat, significant increases in retention were observed after treatment with acetyl-L-carnitine at doses ranging from 1 to 30 mg/kg i.p. In the passive avoidance plus electroconvulsive shock test in the mouse, acetyl-L-carnitine antagonized amnesia at doses ranging from 0.1 to 3 mg/kg i.p.

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Gx 258, a new phenylalkanoic acid derivative, was shown in animal tests to possess potent antiinflammatory, analgesic and antipyretic activity. Its antiinflammatory activity was not mediated via the pituitary-adrenal axis, since it was also effective in adrenalectomized rats. Since large doses of Gx 258, 9-83 times greater than those showing antiinflammatory activity, were required to produce gastrointestinal lesions in rats, Gx 258 appears to have a very good therapeutic index. Its therapeutic index as an antiinflammatory and analgesic agent was 2.3-20.5 times greater than that of the parent compound ibuprofen. Gx 258, like ibuprofen, inhibited the biosynthesis of prostaglandins in vitro.

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As part of a systematic study of the effects of chemical modifications on the antiinflammatory activity of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate, Topicon), a new potent antiinflammatory, a series of derivatives of 2-bromo-6beta-fluoropregna-1,4-diene-3,20-dione was prepared for pharmacological screening. Different synthetic approaches are described. All the synthesized compounds had topical antiinflammatory activity, with no side effects, but were lower in activity than halopredone acetate. Most of them showed topical antiinflammatory activity comparable to that of fluocinolone acetonide. Only two of the synthesized compounds were found to have systemic anti-inflammatory activity comparable to that of betamethasone.

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A series of new halopredone esters has been prepared and screened for local and systemic antiinflammatory activity. High local activity with no side effects, equivalent to that of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon), is obtained when either the 17- or 21-OH of halopredone are benzoylated.

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The topical antiinflammatory activity of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon) has been compared with those of other steroids in a few bioassays in animals. At variance with the reference compounds, halopredone acetate, which exhibited variable potency according to the assay used never displayed substantial systemic effects when locally applied. Even after subcutaneous administration this new steroid did not interfere with adrenal function, carbohydrate and protein metabolism or sodium and potassium excretion. On the basis of the results reported, halopredone acetate may be considered a steroid with potentially high topical antiinflammatory activity and good tolerability.

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Basic derivatives of 6,7-dihydroindolo[1,7-ab][1]benzazepine and 6H-indolo[7,1-cd][1,5]benzoxazepine incorporating the imipramine basic side chain were synthesized and screened for antidepressant activity in mice. With few exceptions, the compounds unsubstituted at C-2 antagonized reserpine-induced ptosis and hypothermia showing negligible anticholinergic and antihistaminic properties. The compound 1-[2-(N-methyl-N-benzylamino)ethyl]-6,7-dihydroindolo[1,7-ab][1]benzazepine had the highest toxicity-activity ratio.

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