Effects of L-DOPA on GABA metabolism in chick brain and retina

The effects of an oral subacute treatment with l-DOPA on GAD, GABA and GABA-T in chick n. basalis (homologous to the mammalian striatum), brain hemispheres, brain-stem and retina were studied. A significant increase in n. basalis GAD activity associated with an increase in GABA content and decrease of GABA-T activity was shown to occur. Similar effects were observed in the brain-stem except for GABA-T which was stimulated. In contrast, in brain hemispheres, l-DOPA produced a decrease in GAD and GABA-T activity. No changes, however, were observed in GAD activity at the retinal level, whereas GABA-T activity was significantly decreased and GABA content increased. In conclusion, the present experiments show that in some areas of the brain the administration of l-DOPA is able to affect GABA turnover.     

Retardation of resynthesis of GABA-transaminase in some brain regions of amygdala-kindled rats

The activities of GABA-transaminase (GABA-T) were examined in several brain regions of amygdala-kindled rats, pretreated either with or without gabaculine, an irreversible GABA-T inhibitor. Histochemical and biochemical studies demonstrated that GABA-T activities decreased significantly in some brain regions 16 h after the gabaculine treatment. In contrast, no such alteration was detected in kindled animals after a 48-h survival period either with or without the pharmacological manipulation. The present results suggest that kindling causes retardation of GABA-T resynthesis in neurons, since the GABA-T activities detected 16 h after the drug treatment are due to newly synthetized enzyme in presumptive GABA neurons but not glial cells.     

Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval

Background: Vigabatrin (Sabril^®) was approved in the USA in mid-2009 for the adjunctive treatment of refractory complex partial seizures and as treatment of infantile spasms. Vigabatrin's more than 30-year history of research and development is condensed into a clinically relevant review pertaining to this 2009 approval. Methods/discussion: A review of the scientific literature was conducted with special focus given to the drug molecule, its mechanism of action, its effects on living systems (e.g., pharmacokinetic, pharmacologic and toxicologic), and its anticipated role among antiepileptic drugs in the USA. Conclusions: The recent approval of vigabatrin makes a significant addition to antiepileptic drug options. The FDA implemented a Risk Evaluation and Mitigation Strategy to control for the possibility of severe adverse drug events.     

Paradoxical blockade of a muscimol response by thip, a GABA agonist and also by GABA-transaminase inhibitors

In a particular strain of mice, relatively large doses of muscimol caused myoclonic jerks of high frequency. This muscimol response was blocked in a dose-dependent manner by a γ-aminobutyric acid (GABA) agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol-hydrate (THIP). Studies using γ-acetylenic GABA and γ-vinyl GABA demonstrated that the blockade of the muscimol-induced jerks caused by these irreversible GABA-transaminase inhibitors closely paralleled the elevation of brain GABA level. It seems that, in this particular strain of mice, muscimol, or one of its metabolites, possibly acts on certain specific binding sites in the central nervous system, eliciting myoclonic jerks and that these receptor sites are different from those to which GABA or THIP binds.

Earlier studies demonstrated the value of the muscimol-induced myoclonic jerks as an animal model for postanoxic action myoclonus. Based on this finding, it is proposed that both THIP and the GABA-transaminase inhibitors might prove to be of value in the management of this clinical condition.     

The effect of the convulsant allylglycine (2-amino-4-pentenoic acid) on the activity of glutamic acid decarboxylase and the concentration of GABA in different regions of guinea pig brain

Intraperitoneal administration of allylglycine to guinea pigs resulted in convulsions approximately 3 hr later. The concentration of GABA and the activity of GAD were significantly reduced in three brain areas, namely the cochlear nucleus, inferior colliculus and cerebral cortex, with the smallest changes being observed in the cortex. There were large in vitro regional variations in the extent of the allylglycine inhibition in brain areas from guinea pig, cat and rat, with those areas rich in GAD activity being least affected. Endogenous GAD activities in the brain regions were found to be inversely correlated with the percentage allylglycine inhibition (P < 0.005). Other inhibitors of GAD activity i.e. NaCl, Zn²⁺ and thiosemicarbazide showed no such regional variation of inhibition. The results suggest that the regional differences in allylglycine inhibition reflect anomalies of the metabolism of the drug per se, and probably do not indicate regional differences in GABA turnover and metabolism.     

Quantitative histochemical study of the effect of benzodiazepine tranquilizers on GABA-transaminase activity in the rat brain

The effect of diazepam and nitrazepam in doses of 0.5, 1, 2.5, and 5 mg/kg on GABA-transaminase activity in the cerebellar cortex and hippocampus of rats was studied by a quantitative histochemical method. Inhibition of GABA-transaminase was found under the influence of both substances. The decrease in activity was particularly marked in the hippocampus after administration of diazepam. It is suggested that the changes observed are the result of inhibition of the enzyme and also of a decrease in the rate of GABA turnover.Department of Pharmacology and Morphological Division, Central Research Laboratory, Academician I. P. Pavlov First Leningrad Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Anichkov). Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 2, pp. 164–166, February, 1979.     

Regulation of GAD expression in rat pancreatic islets and brain by γ-vinyl-GABA and glucose

Summary Glutamic acid decarboxylase (GAD) is an important autoantigen in insulin-dependent diabetes mellitus (IDDM), but little is known about its regulation and function in islet cells. We investigated the effects of the GABA-transaminase inhibitor γ-vinyl-GABA (GVG) on GAD expression in rat islets and brain in vitro and in vivo. In islets incubated in high glucose culture medium there was an increase in GAD activity, GAD65 and GAD67 protein levels compared to low-glucose conditions; however, even in high glucose, GVG still significantly suppressed GAD activity and GAD67 expression. Our observations suggest that glucose and GVG act on GAD in islets through different mechanisms. Quantitative immunohistochemistry of pancreatic sections from rats treated with GVG in vivo using novel monoclonal antibodies specific for GAD65 and GAD67, showed a decrease in GAD67 expression (p < 0.005) relative to untreated rats. The effects of GVG on rat pancreatic islets were very similar to those observed in brain of rats treated with GVG in vivo. In homogenates of cerebral tissue from GVG treated rats containing both membrane-bound and soluble protein GAD67 levels were significantly decreased while GAD65 levels were not significantly changed compared to untreated rats. In contrast, in homogenates of cerebral tissues containing only soluble cytosolic protein, GVG-treatment was also significantly found to decrease GAD65 levels. Taken together, these results suggest that GVG potentially could be of use to decrease GAD expression in islet cells and consequently to deviate/inhibit the autoimmune response against the beta cells seen in IDDM. [Diabetologia (1998) 41: 530–535] Received: 19 August 1997 and in final revised form: 22 December 1997     

Epilepsy in the Renaissance: A survey of remedies from 16th and 17th century German herbals

Ethnopharmacological relevance

Before modern anticonvulsive drugs were developed people in central Europe used herbal remedies to treat epilepsy. Hundreds of different plants for this indication can be found in German herbals of the 16th and 17th centuries. Here we compile these plants and discuss their use from a pharmacological perspective.

Materials and methods

Nine of the most important European herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Mattioli (1590), 103 and 104, Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591, 1678) were searched for terms related to epilepsy, and plants and recipes described for its treatment were documented. We then searched scientific literature for pharmacological evidence of their effectiveness. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied.

Results

Two hundred twenty one plants were identified in the herbals to be used in the context of epilepsy. In vitro and/or in vivo pharmacological data somehow related to the indication epilepsy was found for less than 5% of these plants. Less than 7% of epilepsy remedies are in common with De Materia Medica.

Conclusions

Numerous plants were used to treat epilepsy in the 16th and 17th centuries. However, few of these plants have been investigated with respect to pharmacological activity on epilepsy related targets.     

Vigabatrin: 2008 Update

Vigabatrin (VGB) is a structural analogue of γ‐aminobutyric acid (GABA) that irreversibly inhibits GABA‐transaminase (GABA‐T), increasing brain levels of GABA. VGB is under assessment for treatment of infantile spasms (IS) and refractory complex partial seizures (CPS). Response can be rapid with spasm cessation following approximately 2 weeks of therapy. Patients with symptomatic tuberous sclerosis (TS) and other patients have achieved spasm cessation. Comparison with ACTH has been performed. Patients with refractory CPS have responded as well. Adverse effects and structural findings on imaging occur with VGB treatment. T2 hyperintensities within brain have been observed. Psychotic disorders or hallucinations have occurred rarely. A specific adverse effects is associated VGB, with a peripheral visual field defect (VFD) detected in some patients. Prevalence and incidence of the VGB‐induced peripheral VFD varied depending on the age of the patient and the extent of exposure to VGB, with 25% to 50% prevalence in adults; the prevalence in children was 15% and retinal defect in infants ranged from 15% to 31%. A bilateral nasal defect may be the first clinical indication and may progress to a concentric, bilateral field defect observed in many affected patients; central visual acuity is almost always preserved. The earliest finding of the first abnormal field examination in adults was after 9 months of treatment; with a mean duration of VGB exposure of 4.8 years. In children, the earliest onset of a first abnormal field examination was after 11 months, with a mean time to onset of 5.5 years. The earliest sustained onset of the VGB‐induced retinal defect in infants was 3.1 months. Recommendation: Cognitive, age‐appropriate visual field testing is required at baseline and then repeated at intervals in patients who continue therapy. Infants are tested at baseline and at 3‐month intervals for the first 18 months of treatment, and then every 6 months thereafter. Adults with CPS are tested at baseline and at 6‐month intervals. To select patients who are appropriate for VGB therapy, physicians must consider the benefits of fewer seizures and improved quality of life versus the potential risk of developing a VGB‐induced peripheral VFD. Effectiveness of VGB can be detected within 12 weeks of initiating therapy. There appears to be minimal risk associated with a 2‐ to 3‐month trial of VGB to evaluate effectiveness before there is a demonstrable risk of developing the VGB‐induced peripheral VFD. If patients do not have a clinical benefit from VGB within 12 weeks of treatment initiation, VGB should be discontinued. If patients have a meaningful reduction in seizures or achieve seizure freedom, then the physician and patient or caregiver must determine if the benefits outweigh the potential risk of developing a peripheral VFD. When VGB is prescribed, the patient must be closely monitored for visual field changes. In cases where spasm or seizure improvement is not achieved within 12 weeks of initiation, VGB should be discontinued. In cases where complete spasm cessation, seizure control, or meaningful improvement is achieved within 12 weeks, continued treatment with VGB is warranted; subsequent periodic monitoring for the peripheral VFD is necessary and should be used to mitigate the risk of the defect. The risk of developing the peripheral VFD with short‐term exposure seems to be low, therefore, VGB is an appropriate option for patients with IS or refractory CPS who receive a clinical benefit from its effectiveness, given the clinical consequences of uncontrolled seizures and spasms.     

Time Course of the GABAergic Effects of Vigabatrin: Is the Time Course-of Brain GABA Related to Platelet GABA-Transaminase Inhibition?

PURPOSE: To analyze the time course of the effects of vigabatrin (VGB) on brain gamma-aminobutyric acid (GABA), and its relation with 4-aminobutyrate-2-ketoglutarate amino-transferase (GABA-T) in brain and platelets. METHODS: Blood and brain samples were collected at 4, 24, 48, and 72 h after a single dose and after 3 and 8 days of treatment with 200 mg/kg of VGB in rats. RESULTS: Time courses of the GABAergic effects of VGB were different after single and multiple doses: with multiple doses, the inhibition of brain GABA-T was quicker and longer, the inhibition of platelet GABA-T was greater and longer, the increase in brain GABA was greater, and recovery began earlier. After pooling the data obtained at 4, 24, 48, and 72 h, we observed a power correlation between the increase in brain GABA in individual rats as percentage of the control and both the inhibition of brain GABA-T after a single dose of VGB (r = -0.40; p < 0.05), and the inhibition of platelet GABA-T after 3 days (r = -0.48; p < 0.01) and 8 days of treatment (r = -0.53; p < 0.01). When all data after single and multiple doses were pooled, the increase in brain GABA correlated better with the inhibition of GABA-T in platelets (r = -0.62; p < 0.001) than in brain (r = -0.38; p < 0.001). Platelet GABA-T correlated with brain GABA at 4 h (r = -0.64; p < 0.001) and 24 h (r = -0.66; p < 0.001) but not at 48 and 72 h. CONCLUSIONS: Platelet GABA-T reflects the time course of the increase in brain GABA better than does brain GABA-T after multiple doses of VGB in rats.