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Biomedical subjects

O Kofman

Publications and source records attributed to O Kofman.

At least 37 records · Page 2Linked to original sources
PubMed1995

Follow-up and relapse analysis of an inositol study of depression.

A recent controlled double-blind study of 28 patients treated with 12 gm daily of inositol or placebo revealed significant antidepressant effect for this second messenger precursor. Patients were followed-up by interview and Hamilton Depression Scale 10-12 months after the end of the study. Half of the patients who had responded well to inositol relapsed rapidly after inositol discontinuation whereas none of those who responded to placebo relapsed rapidly after placebo cessation. Klein suggested that true drug responders to tricyclic antidepressants respond slowly and gradually whereas placebo responders improve early in an abrupt fashion. However, in the recent study both inositol and placebo responders improved at similar rates. Hamilton Depression Scale Scores 10-12 months after completion of the study were not significantly different between those who had responded and those who had not responded to inositol or to placebo.

Adult↗
PubMed1995

Inositol treatment in psychiatry.

Inositol, a naturally occurring isomer of glucose, is a key intermediate of the phosphatidyl-inositol (PI) cycle, a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. The suggestion that lithium might treat mania via its reduction of inositol levels led to experiments showing that pharmacological doses of peripheral inositol reverse behavioral effects of lithium in animals and side effects of lithium in man. Cerebrospinal fluid (CSF) levels of inositol are low in depression. An open-label, add-on trial of inositol in depression suggested a beneficial effect. In a subsequent 1-month, parallel-groups, double-blind, placebo-controlled study of 28 patients, inositol was effective as sole therapy for depression (p = .043). Inositol was also effective for panic disorder in a double-blind, random-assignment, placebo-controlled crossover study of 21 patients, with 4 weeks in each phase (p = .02); the effect was comparable to that of imipramine in recent studies.

Clinical Trials as Topic↗
PubMed1994

A new neurotoxin receptor site on sodium channels is identified by a conotoxin that affects sodium channel inactivation in molluscs and acts as an antagonist in rat brain.

The peptide conotoxin TxVIA is selectively toxic to molluscs and slows sodium current inactivation in mollusc neurons. Here we show that TxVIA binds with high affinity to new sites on sodium channels in both mollusc and rat central nervous systems, despite its lack of toxicity to vertebrates. Furthermore, TxVIA protects from the toxic effects of Conus striatus toxin in rat brain. The TxVIA binding site differs from other neurotoxin receptor sites affecting sodium channel inactivation in that binding is not voltage-dependent and undergoes negative allosteric modulation by veratridine. TxVIA therefore represents a novel category of sodium channel probes, designated delta-conotoxins. TxVIA is shown to discriminate between sodium channels in different phyla by activity but not by binding, thus providing a lead for the study of structural elements affecting gating modes of sodium channels.

Animals↗
PubMed1994

High-dose peripheral inositol raises brain inositol levels and reverses behavioral effects of inositol depletion by lithium.

Lithium (Li) reduces brain inositol levels. Berridge has suggested that this effect is related to Li's mechanism of action. It had previously been shown that pilocarpine causes a limbic seizure syndrome in lithium treated rats, and that these lithium-pilocarpine seizures are reversible by intracerebroventricular inositol administration to rats. We now show that although inositol passes the blood-brain barrier poorly, large doses of intraperitoneal (IP) inositol can also reverse Li-pilocarpine seizures. Using gas chromatography, IP inositol can raise brain inositol levels. Demonstration that inositol enters brain after peripheral administration provides a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle.

Animals↗
PubMed1994

Behavioral evidence for the existence of two pools of cellular inositol.

Lithium reduces brain inositol levels by inhibiting inositol monophosphatase. In a previous study it was found that administration of pilocarpine to Li-treated rats causes limbic seizure behavior which can be reversed by i.c.v. myo-inositol but not chiro-inositol, suggesting that this behavior is related to inositol depletion in the PI cycle. Hyponatremia can lower brain inositol and hypernatremia can raise brain inositol. We now report that induction of low brain inositol by hyponatremia followed by pilocarpine did not cause limbic seizures. Induction of high brain inositol using hypernatremia followed by Li-pilocarpine administration did not reverse limbic seizures. These data support the concept that inositol available for P1 synthesis and inositol for osmotic function are sequestered in different cellular pools.

Animals↗
PubMed1993

Ziskind-Somerfeld Research Award 1993. Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression.

Lithium (Li) reduces brain inositol levels by inhibiting the enzyme inositol monophosphatase. The enzyme inositol-1-phosphatase was measured in human red blood cells of controls, Li-free bipolar patients, and Li-treated bipolar patients and was found to be reduced by 80% in Li-treated bipolars, thus supporting the concept that chronic Li at therapeutic concentrations inhibits this enzyme. Two behaviors in rats caused by Li, reduction of rearing, and Li-pilocarpine seizures, are reversed by intracerebroventricular replenishment of inositol. The reversal is stereospecific to the naturally occurring myo-inositol; whereas the stereoisomer L-chiro-inositol is ineffective. The reversal is dose-dependent, requiring a dose consistent with known quantities of brain inositol depletion; and is time-dependent, as inositol must be given 1-8 h before stimulation. High-dose peripheral inositol also reverses the limbic seizures induced by Li-pilocarpine, and using gas chromatography was shown to increase brain inositol levels that had been reduced by Li treatment. Low-dose inositol could be shown to reverse a peripheral Li-induced side effect, polyuria/polydipsia, in rats and in patients treated with Li. A higher dose of inositol markedly reduced Hamilton Depression Ratings in 9 of 11 unipolar major depressive disorder patients previously unresponsive to tricyclics, in an open design, but had no effect on chronic schizophrenics in a controlled double-blind randomized crossover trial. A new inositol monophosphatase inhibitor, a fungal product originally discovered as a complement inhibitor, was found to act like Li and lower the seizure threshold for subconvulsant doses of pilocarpine. These data suggest that inositol monophosphatase inhibition is a key mechanism of Li's therapeutic action and that design of new inositol monophosphatase inhibitors may be a practical strategy to create new compounds with Li-like therapeutic effects.

Adult↗
PubMed1993

Inositol treatment raises CSF inositol levels.

Inositol is a key precursor for synthesis of phosphatidylinositol in a major second messenger signalling system. It is biologically active in syndromes such as respiratory distress syndrome but has been thought to be excluded from CNS by the blood-brain barrier. Oral inositol treatment of 8 patients is shown to significantly increase CSF inositol by almost 70%, suggesting possible CNS therapeutic applications of this compound and possible CNS side-effects of systemic therapy.

Adult↗
PubMed1993

Restoration of brain myo-inositol levels in rats increases latency to lithium-pilocarpine seizures.

Lithium pretreatment in rats potentiates the epileptogenic effects of pilocarpine and other cholinergic agonists. In order to determine if this effect of lithium could be reversed by myo-inositol, rats were pretreated with intracerebroventricular (ICV) injections of myoinositol, artificial CSF or L-chiro-inositol. Lithium chloride, 3 meq/kg was administered intraperitoneally 20-24 h prior to the subcutaneous injection of pilocarpine, 20 or 30 mg/kg. In both experiments, myo-inositol significantly prolonged the latency to the appearance of clonic seizures and lowered the pilocarpine seizure score. myo-Inositol prevented the development of clonic seizures in 50% of the rats receiving pilocarpine, 20 mg/kg. The levels of cortical myo-inositol in rats injected with myo-inositol were approximately double those of the CSF and L-chiro-inositol groups.

Animals↗
PubMed1993

Central and peripheral minocycline suppresses motor activity in rats.

Minocycline (MIN) HCl is a tetracycline derivative previously shown to inhibit agonist-induced accumulation of cyclic adenosine monophosphate (cAMP) in vitro and suppress motor activity and amphetamine-induced hyperactivity in rats following SC injection. The present study examined the effect of IV and intracerebral MIN on baseline activity and amphetamine-induced hyperactivity. IV MIN suppressed both types of activity in doses of 100 and 150 mg/kg. When injected ICV, MIN (50 micrograms/2 microliter) suppressed the increase in rearing elicited by amphetamine but did not affect baseline activity. MIN did not attenuate the behavioral suppression induced by the cAMP phosphodiesterase inhibitor rolipram. MIN apparently has centrally mediated effects on motor activity in rats; however, it is not yet possible to associate MIN's behavioral effects with its ability to inhibit agonist-induced stimulation of cAMP.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

The effect of peripheral inositol injection on rat motor activity models of depression.

Myo-inositol is an important precursor in cellular second-messenger synthesis. It has been reported to be reduced in the cerebrospinal fluid of depressed patients and to reverse a specific effect of Li on rat behavior when given intracerebroventricularly (i.c.v.). However, myo-inositol enters the brain poorly when given peripherally, and its effects on normal rat brain have not been well studied. A series of experiments examined the effect of intraperitoneal inositol in high doses on locomotor activity, on amphetamine-induced hyperactivity, on apomorphine-induced stereotyped behavior, and on pilocarpine-induced behaviors in rats. In addition, the behavioral effect of i.c.v. inositol was compared to that of a control stereoisomer in untreated and lithium-treated rats. Few effects of peripheral myo-inositol were found in these models. However, peripheral inositol in high doses given to rats exhibiting Li-pilocarpine seizures showed that i.p. inositol could prevent these behaviors, confirming that peripheral inositol may have antidepressant potential in appropriate models.

Amphetamine↗
PubMed1992

Failure of addition of lithium to imipramine to enhance activity in rats or mood in normal volunteers.

Lithium powerfully augments the effects of imipramine in resistant depression. We treated four groups of rats for five weeks with (1) saline alone, (2) saline followed by lithium, (3) imipramine alone, and (4) imipramine followed by lithium. There was no augmentation of activity by lithium. Normal human volunteers took imipramine 75 mg daily for three weeks, followed by imipramine 75 mg daily together with lithium 900 mg daily for another ten days. There was no elevation of mood after the addition of lithium. Lithium augmentation of antidepressants apparently requires a pre-existing neurochemical-behavioral disturbance.

Affect↗
PubMed1991

Myo-inositol attenuates two specific behavioral effects of acute lithium in rats.

Acute and chronic lithium treatment reduces levels of brain myo-inositol in rats. Several biological effects of lithium can be reversed in vitro by addition of myo-inositol. The ability of myo-inositol to reverse behavioral effects of lithium was tested using chronic inositol administration or acute intracerebroventricular (i.c.v.) injections. Chronic myoinositol elevated activity during the first 10 min in an open field, but did not reverse lithium-induced hypokinesia. Myo-inositol (i.c.v.) reversed the suppression of rearing behavior 24 hrs after an acute dose of lithium (5 mEq/kg) but did not attenuate hypokinesia 24 hrs after a high dose of lithium (10 mEq/kg). Myo-inositol, but not the inactive isomer chiro-inositol (i.c.v.), also significantly prolonged the latency to clonus in the lithium pilocarpine seizure model. These studies suggest that reduction of brain myo-inositol may be a critical mechanism for the behavioral effects of lithium.

Animals↗
PubMed1990

Intracerebroventricular myo-inositol antagonizes lithium-induced suppression of rearing behaviour in rats.

Several biological effects of lithium have been reversed by in vitro myo-inositol. To determine if intracerebroventricular myo-inositol would reverse behavioural effects of lithium, rats were injected with 5 meq/kg lithium chloride or sodium chloride and injected intracranially with myo-inositol (10 mg) or artificial CSF 24 h and 15 min prior to measurement of activity in an automated activity monitor. Myo-inositol alone had no significant effect on behaviour, but significantly reversed suppression of rearing activity by lithium.

Analysis of Variance↗
PubMed1990

Differential effects of atropine, procaine and dopamine in the rat ventral tegmentum on lateral hypothalamic rewarding brain stimulation.

Microinjections of the muscarinic antagonist, atropine, of dopamine, or of the local anesthetic, procaine, in the ventral tegmentum elevated frequency thresholds for lateral hypothalamic self-stimulation. The largest and most robust effects were observed following atropine (30 or 60 micrograms) microinjections. The most sensitive sites for the atropine effect were near dopamine cells. In order to determine if the effects of atropine can be reversed by pretreatment with a cholinergic agonist, carbachol (1-3 micrograms) was microinjected 15 min prior to atropine. Carbachol pretreatment attenuated the frequency threshold elevation of atropine by 47-95%. Since atropine is a local anesthetic, the effects of procaine on self-stimulation thresholds were tested as well. Procaine (100 or 250 micrograms) in ventral tegmentum elevated frequency thresholds by much less than atropine. Therefore, while atropine attenuates reward primarily through blockade of muscarinic receptors, the local anesthetic effect of atropine may enhance the threshold elevation. Dopamine (1-10 micrograms) also elevated frequency thresholds, but when dopamine injections were repeated daily, the threshold elevations were attenuated. This attenuation contrasted with the robust effects of atropine, and may reflect the development of autoreceptor subsensitivity. Hence, both dopaminergic and muscarinic receptors in ventral tegmentum are involved in lateral hypothalamic brain stimulation reward.

Animals↗
PubMed1990

Inhibition by antibiotic tetracyclines of rat cortical noradrenergic adenylate cyclase and amphetamine-induced hyperactivity.

Two antibiotic tetracyclines, demeclocycline (DMC) and minocycline, share several biochemical and behavioral properties with lithium (Li). DMC inhibited both noradrenaline- and chloradenosine-sensitive cyclic AMP accumulation in rat cerebral cortical slices both in vitro and ex vivo following two weeks of chronic dietary treatment. Minocycline, a lipophilic tetracycline, produced similar results in vitro. Both DMC and minocycline reduced open-field activity levels in rats following acute treatment, four hours prior to testing. Moreover, both drugs inhibited amphetamine-induced hyperactivity in the open field. Chronic treatment with 0.4% and 0.8% dietary DMC for two weeks attenuated amphetamine hyperactivity without affecting baseline activity levels in the open field. Neither DMC nor minocycline attenuated apomorphine-induced stereotypy at doses that attenuated amphetamine hyperactivity, a profile which is similar to that of lithium. Unlike lithium, however, DMC did not reverse reserpine-induced hypoactivity.

2-Chloroadenosine↗