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Successful treatment of epilepsy with serotonin reuptake inhibitors: proposed mechanism
No full textThe widely used antidepressants Specific
Serotonin Reuptake Inhibitors (SSRI) have been tried with
success as anticonvulsants in cases of nonsymptomatic
epilepsy. This attempt was performed on the basis of
experimental data suggesting the involvement of impairments
of the serotonin system in the genesis of epilepsy.
This overview summarizes the clinical data and presents
biochemical and neurochemical evidences suggesting the
mechanism of the therapeutic effects of SSRI in nonsymptomatic
epilepsy. In particular, studies on blood-borne
neutral amino acids and platelet serotonin transporter
(SERT) in epileptics suggest: (a) That a decreased brain
availability of tryptophan may be related to some types of
epilepsy. (b) That reduction of the density of SERT may be
a homeostatic reaction in the brain following epileptic
seizures. The possibility that derangements in the brain serotonin
system may be involved in the generation of epileptic
seizures has been discussed since long time ago [1]. Over
the years, this possibility has been tested in animal models,
among which the GEPR (genetically prone rat) model [2,
3]. Even more importantly, links between noradrenaline
and serotonin deficiencies and the epileptic human brain
have been found [3]. This theory is at odds with the initial
suggestions that monoamine uptake blocking antidepressants
are convulsants [4–6]. The lack of contradiction of
this circumstance and the noradrenaline/serotonin theory in
epilepsy has been discussed at length by Jobe and
Browning [3]. The main point discussed is that doses much
above the antidepressant therapeutic range are those
leading to convulsions, thus eliminating the possibility that
potentiation of the amine function may be the basis for the
proconvulsant effect.
The core of the theory discussed by Jobe and Browning
[3] is that epilepsy and affective illnesses have a common
background. In their view, the two illnesses have different
intrinsic fabricators, i.e. neuronal circuits which actually
initiate and sustain dysfunctional episodes. However, they
share common exterior defensive shields which are made
up of circuits using noradrenaline and serotonin and protect
the system from a deranged function of the intrinsic fabricators.
This may lead to either the epileptic pathology or
affective disorders, such as depression, according to the
particular fabricator involved. These ideas have been
tested by those authors in the genetically epilepsy prone rat
model GEPR.
The idea that serotonin could be involved in epileptogenesis
was already present in the early 1990s [7–10]. Even
much earlier works had shown in animal models that 5-hydroxytryptophan, a serotonin precursor, has an
antiepileptic effect [e.g. 11, 12].
Our group thus set out at that time to test in a clinical
trial whether potentiation of the brain serotoninergic
system could be helpful in patients with drug refractory
epilepsy. Fluoxetine was initially added to ongoing treatments
with carbamazepine or carbamazepine/phenobarbital
and later this was repeated with cytalopram in another
group of patients. Later over the years, we tested in epileptic
patients and in controls the blood levels of the
serotonin precursor tryptophan and of the neutral amino
acids able to compete for the same carrier for the passage
of the blood–brain barrier (BBB).
In addition, we studied the status of the serotonin
transporter (SERT) of the venous blood platelets in epileptic
patients vs. controls.
In the present overview we try and discuss the overall
picture emerging from these approaches. The results do not
contradict the theoretical framework proposed by Jobe and
Browning [3]
A subtype of the gamma-aminobutyric acid(B) receptor regulates cholinergic twitch response in the guinea pig ileum
No full text
Is the Platelet Serotonin Transporter Different in Venous vs. Arterial Blood?
No full textThe binding of labelled paroxetine to the serotonin transporter (SERT) of platelet membranes has been studied in both venous and mixed venous/arterial blood of the rat. In addition, we studied the inhibition of paroxetine binding to SERT by quipazine and N-methyl-quipazine (NMQ). The results indicate differences in affinity for the two test drugs, quipazine and NMQ, in venous vs. mixed venous/arterial blood. This suggests different post-translational modifications of SERT in platelets of arterial vs. venous blood
Sex differences in human lymphocyte Na,K-ATPase as studied by labeled ouabain binding
No full textPhosphocreatine can to some extent compensate for the lack of ATP synthesis that is caused in the brain by deprivation of oxygen or glucose. Treatment of in vitro rat hippocampal slices with creatine increases the neuronal store of phosphocreatine. In this way it increases the resistance of the tissue to anoxic or ischemic damage. In in vitro brain slices pretreatment with creatine delays anoxic depolarization (AD) and prevents the irreversible loss of evoked potentials that is caused by transient anoxia, although it seems so far not to be active against milder, not AD-mediated, damage. Although creatine crosses poorly the blood-brain barrier, its administration in vivo at high doses through the intracerebroventricular or the intraperitoneal way causes an increase of cerebral phosphocreatine that has been shown to be of therapeutic value in vitro. Accordingly, preliminary data show that creatine pretreatment decreases ischemic damage in vivo
Catatonic features in major depression relieved by electroconvulsive treatment: parallel evaluation of the status of platelet serotonin transporter
No full textThe aim of this research was to follow parallelly the clinical status of a patient and
the dynamics of the serotonin transporter (SERT), a likely player in the effect of
electroconvulsive treatment (ECT), a powerful tool against deep depression.
A patient affected by major depression with catatonic features, not responding
to pharmacological therapy, underwent ECT. Evaluations of the binding of labelled
paroxetine to venous blood platelet SERT were parallel to the assessments of clinical
improvements.
The density of platelet SERT, starting from a low level before ECT, displayed
an initial steep increase peaking the day after the third electroconvulsive session (5
days after the start of ECT). This was followed by a rapid decrease, which seemed
to precede the process of clinical recovery.
These results were found in a case of unavoidable ECT treatment. If
generalizable, they suggest interesting ideas about the still mysterious mechanism
of ECT antidepressant action. Electroconvulsive therapy (Cerletti, 1941, 1950) is recognized as the most
efficacious treatment in cases of major depressions accompanied by catatonic
features with a life threat for the patient (APA, 2001; Abrams, 2002).
We describe a case of an elderly woman affected by major depression
and catatonic signs successfully treated with ECT. The course of the eight
electroconvulsive treatment (ECT) sessions at alternate days was accompanied
by marked changes in the density of platelet membrane serotonin transporter
(SERT)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Ethanol Inhibits the Binding of Substance P to Rat Brain Cortex NK1 Receptors
No full textThe binding of 125I-labeled substance P (SP) to rat brain cortex membranes has been studied under control conditions and in the presence of ethanol. The binding of SP at low concentrations (20-1000 pM) gave two components, one with a KD value of 80 pM and another one with a KD of 500 pM. The higher-affinity component is due to NK1 receptors, as confirmed by the inhibition of the SP binding by the rodent NK1 specific agonist [Sar9 Met(O2)11]SP. Ethanol (1.7 mM) added to the binding assays inhibited by more than 50% the specific binding at a very low SP concentration (20 pM); however, it had no effect at SP concentrations ranging from 50 to 120 pM. This suggests a decrease by ethanol of the affinity of SP to the NK1 receptors involved in this binding component. The ethanol effect disappeared at [EtOH] ≤0.17 mM
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