Sodium Divalproate in Low Alternating Daily Doses for Migraine Prevention: A Retrospective Study.

BACKGROUND AND OBJECTIVE: Sodium divalproate is an effective neuromodulator for migraine prevention. Recommended doses vary from 1,000 to 1,500 mg/day, which may provoke unpleasant side effects as weight gain, tremor, and hair loss. Some patients do respond to lower doses even used once daily in ER presentations, but alternating low daily doses was never studied so far. The aim of this study was to evaluate the adherence, the tolerability, and the efficacy of sodium divalproate (SD) in low alternating daily doses for migraine prevention in patients of a tertiary center. METHODS: Consecutive migraineurs from a tertiary center to whom SD was prescribed as monotherapy from January 2017 until September 2018 were studied retrospectively. The doses were 250 mg alternated with 500 mg and were used based on the treating physician expertise and previous experience with tolerability issues when using higher doses. Headache frequency compared to baseline, adherence expressed by returning to a visit after 2 and 4 months and side effects reported by the patients, were evaluated. RESULTS: Sixty-eight patients (53 women and 15 men, aged 18-58) were included. The average headache frequency (HF) during baseline was decreased from 8.2 to 5.1 headache days/month among the 50 out of 68 patients returning at 2 months (adherence rate 73.5%). Weight gain was reported by 15 patients (30%, mean 2.1 kg). At 4 months, HF was reduced to 4.2 days/month (adherence rate 61.8%, n = 42) and weight gain reported by 18 patients (42.8%, mean 2.3 kg). CONCLUSIONS: Despite the retrospective open design, which cannot allow definitive conclusions, SD in low alternating daily doses seems to be effective as with higher doses, but still induce modest weight gain. Controlled studies are necessary to confirm these observations.

Effect of Rivastigmine Augmentation in Treatment of Male Patients With Combat-Related Chronic Posttraumatic Stress Disorder: A Randomized Controlled Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is one of the chronic and disabling psychiatric disorders, particularly in combat veterans. In a case series, rivastigmine was suggested to be an effective augmentation in treatment of PTSD. The aim of the present study was to evaluate this finding in a randomized controlled trial. METHOD: A 12-week, double-blind, placebo-controlled clinical trial was performed on 36 male patients (aged 42-60 years) diagnosed with chronic, combat-related PTSD. Subjects were screened for apparent cognitive deficits by means of Mini-Mental State Examination. All patients received selective serotonin reuptake inhibitors plus sodium valproate for 4 weeks and then reevaluated. Subjects who did not show adequate response were randomly assigned into 3 groups receiving rivastigmine (up to 6 mg/d), placebo, or the prior treatment regimen. Efficacy of medication was measured by administering PTSD Check List-Military Version at baseline and weeks 2, 4, 8, and 12. Collected data were analyzed by analysis of variance and repeated measurement. Reported differences were considered significant at the level of 0.05 or less. RESULTS: The 3 groups showed statistically significant reductions in the total PTSD Check List-Military Version, avoidance subscale, and the reexperience subscale but not in the hyperarousal subscale. No significant differences were found between the 3 groups. CONCLUSIONS: In contrast to the previous case series, findings of the current study did not support the efficacy of adjunctive rivastigmine in treatment of PTSD. This hypothetically could be due to the fact that all the study's subjects scored higher than 25 on Mini-Mental State Examination.

Striatum and globus pallidus control the electrical activity of reticular thalamic nuclei.

Through GABAergic fibers, globus pallidus (GP) coordinates basal ganglia global function. Electrical activity of GP neurons depends on their membrane properties and afferent fibers, including GABAergic fibers from striatum. In pathological conditions, abnormal electrical activity of GP neurons is associated with motor deficits. There is a GABAergic pathway from the GP to the reticular thalamic nucleus (RTn) whose contribution to RTn neurons electrical activity has received little attention. This fact called our attention because the RTn controls the overall information flow of thalamic nuclei to cerebral cortex. Here, we study the spontaneous electrical activity of RTn neurons recorded in vivo in anesthetized rats and under pharmacological activation or inhibition of the GP. We found that activation of GP predominantly diminishes the spontaneous RTn neurons firing rate and its inhibition increases their firing rate; however, both activation and inhibition of GP did not modified the burst index (BI) or the coefficient of variation (CV) of RTn neurons. Moreover, stimulation of striatum predominantly diminishes the spiking rate of GP cells and increases the spiking rate in RTn neurons without modifying the BI or CV in reticular neurons. Our data suggest a GP tight control over RTn spiking activity.

The lesion of dorsolateral funiculus changes the antiallodynic effect of the intrathecal muscimol and baclofen in distinct phases of neuropathic pain induced by spinal nerve ligation in rats.

The abnormal firing of damaged primary afferents and the changes in the central nervous system (CNS) play important role in the initiation and maintenance phases of neuropathic pain. These phases of neuropathic pain involve changes in the GABAergic control of descending pathways that travel through the dorsolateral funiculus (DLF). The present study shows that unilateral DLF lesion increased the antiallodynic effect of muscimol (0.2µg/5µL) (a GABAA receptor agonist) in the initiation, but not maintenance phase of the mechanical allodynia induced by a spinal nerve ligation (SNL) of the ipsilateral hindpaw of rats. The unilateral DLF lesion increased the antiallodynic effect of baclofen (0.8µg/5µL) (a GABAB receptor agonist) in the initiation phase and reduced your effect in the maintenance phase of the mechanical allodynia induced by a spinal nerve ligation (SNL) of the ipsilateral paw of rats. The unilateral DLF lesion significantly reduced the proallodynic effect of an intrathecal injection of phaclofen (30µg/5µL) (a GABAB receptor antagonist), but not bicuculline (0.3µg/5µL) (a GABAA receptor antagonist). The effect of DLF lesion on the proallodynic effect of phaclofen was observed in the maintenance, but not in the initiation phase of the mechanical allodynia induced by SNL. We than conclude that the spinal GABAergic neurotransmission is negatively modulated by DLF using GABAA and GABAB receptors, in the initiation phase of mechanical allodynia induced by SNL. In addition, the integrity of DLF is necessary for the effectiveness of GABAergic transmission that occurs via spinal GABAB, but not GABAA receptors, in the maintenance phase of mechanical allodynia induced by SNL.

Cardiovascular and behavioral effects produced by administration of liposome-entrapped GABA into the rat central nervous system.

Liposomes are nanosystems that allow a sustained release of entrapped substances. Gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter of the central nervous system (CNS). We developed a liposomal formulation of GABA for application in long-term CNS functional studies. Two days after liposome-entrapped GABA was injected intracerebroventricularly (ICV), Wistar rats were submitted to the following evaluations: (1) changes in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) to ICV injection of bicuculline methiodide (BMI) in anesthetized rats; (2) changes in cardiovascular reactivity to air jet stress in conscious rats; and (3) anxiety-like behavior in conscious rats. GABA and saline-containing pegylated liposomes were prepared with a mean diameter of 200 nm. Rats with implanted cannulas targeted to lateral cerebral ventricle (n = 5-8/group) received either GABA solution (GS), empty liposomes (EL) or GABA-containing liposomes (GL). Following (48 h) central microinjection (2 µL, 0.09 M and 99 g/L) of liposomes, animals were submitted to the different protocols. Animals that received GL demonstrated attenuated response of RSNA to BMI microinjection (GS 48 ± 9, EL 43 ± 9, GL 11 ± 8%; P < 0.05), blunted tachycardia in the stress trial (ΔHR: GS 115 ± 14, EL 117 ± 10, GL 74 ± 9 bpm; P<0.05) and spent more time in the open arms of elevated plus maze (EL 6 ± 2 vs. GL 18 ± 5%; P = 0.028) compared with GS and EL groups. These results indicate that liposome-entrapped GABA can be a potential tool for exploring the chronic effects of GABA in specific regions and pathways of the central nervous system.

RuBiGABA-2: a hydrophilic caged GABA with long wavelength sensitivity.

We have devised a new caged GABA based on ruthenium bipyridyl coordination chemistry. This phototrigger delivers GABA upon irradiation with wavelengths up to 532 nm undergoing heterolytic photocleavage, in a clean and very fast (a few nanoseconds) photoreaction. With an absorptivity coefficient ε(MAX) = 5300 M(-1) cm(-1) at 447 nm and a quantum efficiency φ ~ 0.09, RuBiGABA-2 is among the most active caged-GABAs, especially at long wavelengths. This highly hydrophilic caged GABA can be synthesized in a simple one-pot reaction. The synthesis, chemical characterization and photochemical properties are presented. Finally, the usefulness of this caged compound is demonstrated by photodelivering free GABA on leech motoneurons.

GABAergic processes within the median preoptic nucleus promote NREM sleep.

GABAergic mechanisms in the preoptic region of the hypothalamus (POA) have been implicated in the generation and maintenance of NREM (quiet) sleep. We recently reported that neurons in the median peptic nucleus (MnPN) in the POA of the cat are selectively activated during NREM sleep. In the present study, we explored the hypothesis that NREM sleep is controlled by GABAergic mechanisms within the MnPN. Consequently, adult cats were utilized to determine GABA immunorreactivity within the MnPN and to examine the effects on sleep of the microinjection of a GABA(A) agonist (muscimol) and a GABA(A) antagonist (bicuculline) into this area. GABAergic neurons were present throughout the MnPN. Compared with control microinjections, after the application of muscimol, the time spent in NREM sleep (59.8±7.5 min) and REM sleep (6.9±4.7 min) decreased compared with control microinjections (103.8±5.2 and 20.2±4.3 min, respectively; P<0.005). In contrast, bicuculline microinjections increased only NREM sleep time (103.0±23.0 vs 77.7±23.7 min; P<0.05). These results demonstrate that GABAergic processes within the MnPN are involved in the generation and maintenance of sleep, especially NREM sleep.

Opposite effects of low and high doses of the gastrin-releasing peptide receptor antagonist RC-3095 on memory consolidation in the hippocampus: possible involvement of the GABAergic system.

Although the gastrin-releasing peptide receptor (GRPR) has recently emerged as a system importantly involved in regulating memory formation, the role of hippocampal GRPRs in memory remains controversial. The present study examined the effects of GRPR antagonism on memory consolidation in area CA1 of the hippocampus. Male Wistar rats received bilateral infusions of the GRPR antagonist [D-Tpi6, Leu13 psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095; 1, 3, or 10 microg/side) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. RC-3095 at 1 microg impaired, whereas the dose of 10 microg enhanced, 24-h IA retention. A second experiment showed that the RC-3095-induced enhancement of memory consolidation was prevented by pretraining infusion of an otherwise ineffective dose of the gamma-aminobutyric acid type A (GABA(A)) receptor agonist muscimol. The results indicate that high doses of GRPR antagonists can induce enhancement of memory consolidation in the hippocampus. In addition, the memory-enhancing effect of GRPR antagonists might be mediated by inhibition of GABAergic transmission.

[Effect prolonged GABAergic activation on the pubertal development of female rats]. / Efecto de la activación GABAérgica sobre la maduración sexual en ratas hembras peripuberales.

We evaluated, in immature female rats, the effect of the GABAergic system on the reproductive axis and on pubertal development. Initially, using a prolonged treatment with aminooxyacetic acid (AOAA), increasing hypothalamic GABA (p < 0.002), and decreasing GnRH and glutamate content (p < 0.05 and < 0.02). Treated rats showed diminished serum LH (p < 0.05) and estradiol (p < 0.005) levels. Vaginal opening occurred at 30.8 +/- 0.6 days in controls, and at 36.7 +/- 0.98 days in AOAA-treated rats. Acute treatment with AOAA resulted in a decreased GnRH and glutamate output, and in an increased taurine release from superfused hypothalamic fragments. This effect was mimicked by the GABA-A and GABA-B agonists. The activation of the GABAergic system during postnatal days 23-29 significantly restrains the hypothalamo-pituitary-ovaric axis and delays the onset of puberty. The existence of a physiological cross-talk between excitatory and inhibitory amino acid neurotransmitters regulating GnRH release during the onset of puberty is postulated.

Efecto de la activacion gabaergica sobre la maduracion sexual en ratas hembras peripuberales / Effect prologed gabaergic activation on the pubertal development of female rats

Evaluamos 1) efecto del tratamiento prolongado (días 23-29 postnatales) con ácido aminooxiacético (AAOA) sobre el desarrollo puberal en ratas hembra; este tratamiento aumentó el contenido de GABA (p< 0.002), disminuyendo el de GnRH y glutamato (p < 0.05 y < 0.02) en hipotálamo. La LH (p < 0.05) y el estradiol (p < 0.005) séricos cayeron. La apertura vaginal fue a los 30.8 + 0.6 días en los controles, y a los 36.7 + 0.98 días en las tratadas (p < 0.0001). 2) A los 30 días, el tratamiento agudo con AAOA redujo la liberación ex vivo de GnRH y de glutamato la de taurina. Este efecto fue similar al observado agregando al medio agonistas GABA-A y B. Conclusiones: la activación peripuberal del sistema GABAérgico frena el eje reprodutor, produciendo un retraso en el desarrollo. Esto podría atribuirse a la existencia, en esta etapa, de interrelaciones fisiológicas entre los aminoácidos que regulan la secreción de GnRH (GABA, glutamato, taurina).

Efecto de la activacion gabaergica sobre la maduracion sexual en ratas hembras peripuberales / Effect prologed gabaergic activation on the pubertal development of female rats

Evaluamos 1) efecto del tratamiento prolongado (días 23-29 postnatales) con ácido aminooxiacético (AAOA) sobre el desarrollo puberal en ratas hembra; este tratamiento aumentó el contenido de GABA (p< 0.002), disminuyendo el de GnRH y glutamato (p < 0.05 y < 0.02) en hipotálamo. La LH (p < 0.05) y el estradiol (p < 0.005) séricos cayeron. La apertura vaginal fue a los 30.8 + 0.6 días en los controles, y a los 36.7 + 0.98 días en las tratadas (p < 0.0001). 2) A los 30 días, el tratamiento agudo con AAOA redujo la liberación ex vivo de GnRH y de glutamato la de taurina. Este efecto fue similar al observado agregando al medio agonistas GABA-A y B. Conclusiones: la activación peripuberal del sistema GABAérgico frena el eje reprodutor, produciendo un retraso en el desarrollo. Esto podría atribuirse a la existencia, en esta etapa, de interrelaciones fisiológicas entre los aminoácidos que regulan la secreción de GnRH (GABA, glutamato, taurina). (AU)

Interaction between alpha-MSH and gabaergic agents upon striatal cAMP levels: an in vitro model.

We have tried to investigate the possible interaction between the gabaergic system and alpha-MSH at a cellular level in an in vitro model of male albino rats tissue slices containing accumbens and caudate-putamen nuclei. Alpha-MSH alone increases cAMP levels, as does diazepam and phaclofen; however, these effects were blocked by SCH-23390. Both flumazenil and baclofen induced a decrease in the cAMP content. When both alpha-MSH and gabaergic agents were incubated together, cAMP levels were modified. It can be assumed that cAMP production by the neuropeptide and the gabaergic agents could be linked to the activation of dopaminergic D1 receptors. The latter receptors had no prominent effect on the interaction between alpha-MSH and the GABA agonists and antagonists. In summary, our results suggested that alpha-MSH and GABA system could be biochemically linked to produce a cellular effect.

Effect of manipulation of the GABA system on dopamine-related behaviors

The interaction between GABAergic and dopaminergic system within the central nervous system was investigated in rats using the open-field apparatus and apomorphine-induced stereotypy, and in mice using haloperidol-induced catalepsy. The single intraperitoneal adminsitration of baclofen 3.0 mg/kg, 4,5,6,7-tetrahydroisoxasolo-(5,4-c) piridin-3-ol (THIP) 10.0 mg/kg and picrotoxin 2.0 mg/kg decreased both ambulation and rearing frequencies of the rats in the open-field; only the GABA agonists increased the duration of animal immobility. THIP (10.0 mg/kg) increased the duration of haloperidol-induced catalepsy. For apomorphine-induced stereotypy, baclofen 3.0 mg/kg and picrotoxin 1.0 mg/kg induced a significant leftward displacement of the control dose-response curve constructed for apomorphine (0.1-10 mg/kg) in relation to the control. In addition, baclofen, THIP, picrotoxin and 3-mercaptopropionic acid (3-MPA) 10.0 mg/kg decreased both rearing and sniffing behaviors elicited by apomorphine and increased licking and/ or gnawing. Different mechanisms seem to be involved in the similar effects induced by GABA agonists and antagonists. Picrotoxin induced stereotyped movements per se with a dose-dependent effect, but baclofen and THIP did not. The present data suggest that GABA manipulation facilitates the progressive activation of the different dopaminergic pathways involved in stereotyped behaviors, thus increasing those stereotyped components (gnawing and licking) that appear after a high level of activation of dopaminergic pathways