Pharmacological Use of Gamma-Aminobutyric Acid Derivatives in Osteoarthritis Pain Management: A Systematic Review

Background Pain is the major complication of osteoarthritis (OA) patients and is a decisive symptom for medical intervention. Gamma-aminobutyric acid (GABA) derivatives are optional painkillers but not widely used in pain management of OA patients. We synthesized the efficacy and safety of GABA derivatives for OA pain management. Methods We searched Medline, Cochrane CENTRAL, Embase, and ClinicalTrals.gov from inception to 13 October 2021 and included randomized controlled trials (RCTs) comparing the efficacy and safety of GABA derivatives with placebo or standard control in OA pain management. Two independent reviewers extracted data and assessed these studies for risk of bias using Cochrane Collaboration’s tool for RCT. Results In total, three eligible RCTs (n=3) meeting the eligibility criteria were included. Among these RCTs, one focused on hand OA pain management, while two RCTs focused on knee OA. In hand OA, pregabalin reduced numerical rating scale (NRS) score and the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain score significantly compared with placebo, and caused 55 AEs. In knee OA, pregabalin reduced visual analogue scale (VAS) score and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score significantly with no recorded adverse event (AE). Meanwhile, in knee OA, gabapentin reduced both VAS score and WOMAC pain score compared with acetaminophen and caused 9 AEs. Conclusions GABA derivates are effective and safe in OA pain management. However, future researches with large sample size are needed to further prove the efficacy of GABA derivates in OA pain control. Trial registration: CRD42021240225.

Effect of early and late pharmacological correction with GABA derivatives on cognitive disorders in offspring of rats with experimental preeclampsia

BACKGROUND: Preeclampsia is a serious complication of pregnancy which augments the risk of cognitive disorders in the offspring at different stages of life. Presently, there are no methods with proven effectiveness for correction of post-hypoxic disorders in children of mothers with preeclampsia. AIM: To assess the cognitive functions of the offspring of rats with experimental preeclampsia (EP) through early (40th to 70th day of life) and late (24th to 25th month of life) pharmacological correction with gamma aminobutyric acid (GABA) derivatives: Succicard, Salifen, Phenibut, and the drug of comparisonPantogam. MATERIALS AND METHODS: EP was modeled by replacing drinking water with 1.8% sodium chloride solution in rats from the first day of pregnancy to delivery. In the offspring, short-term and long-term memory was studied at the age of 34, 1819, and 2526 months in the Novel object recognition test and Barnes Maze test. The functioning of the GABAergic and dopaminergic systems (which play an essential role in the development of memory) was evaluated by cases of convulsions after administering corazol at a dose of 20 mg/kg intraperitoneally (model of corazol kindling) and by haloperidol-induced catalepsy (haloperidol at a dose of 0.3 mg/kg intraperitoneally), respectively. RESULTS: Early and late pharmacological correction with GABA derivativessuccicard, Salifen, Phenibut, and comparison drug, Pantogamneutralized the negative effect of EP on the function of GABAergic and dopaminergic systems in the offspring of the experimental groups. Therapy with Succicard in puberty and long-term periods of life contributed to the improvement of short-term and long-term memory in the offspring of rats with EP. Thus, it could be reasonable enough to develop a drug against cognitive disorders in children of mothers with preeclampsia. CONCLUSION: In the offspring of rats with EP, short-term and long-term disorders of memory in the functioning of the GABAergic and dopaminergic systems were noted in the early and late stages of the individual development. Pharmacological correction with GABA derivatives improves cognitive processes and the functioning of neurotransmitter systems in the offspring of rats with complicated pregnancy. The highest effectiveness was demonstrated by succicard, and was comparable with or superior to the Pantogam (standard drug).

НОВЫЕ ПОТЕНЦИАЛЬНЫЕ ПРОТИВОСУДОРОЖНЫЕ СРЕДСТВА В РЯДУ N-ПАРА-ЗАМЕЩЕННЫХ НЕЙРОАМИНОКИСЛОТ И ИХ ЛИТИЕВЫХ ПРОИЗВОДНЫХ / NEW POTENTIAL ANTICONVULSANT COMPOUNDS IN A NUMBER OF N-PARA-SUBSTITUTED NEUROAMINO ACIDS AND THEIR LITHIUM DERIVATIVES

Изучены степени противосудорожной активности некоторых N-пара-замещенных производных γ-аминомасляная кислоты и их литиевых солей. Все исследованные соединения проявляют противосудорожную активность по антагонизму с коразолом и тиосемикарбазидом. Новые синтезированные производные ГАМК представляют биологическую ценность как новые нейротропные вещества, обладающие противосудорожными свойствами. / The degrees of anticonvulsant activity of some N-para-substituted derivatives of γ-aminobutyric acid and their lithium salts were studied. All studied compounds exhibit anticonvulsant activity in antagonism with corazole and thiosemicarbazide. Newly synthesized GABA derivatives are of biological value as new neurotropic substances with anticonvulsant properties.

γ-Aminobutyric Acid and Derivatives Reduce the Incidence of Acute Pain after Herpes Zoster - A Systematic Review and Meta-analysis

Herpes zoster (HZ) causes considerable pain and distress, and γ-Aminobutyric acid (GABA) and its derivatives are assumed to control this, but the available data are inconsistent. This meta-analysis and systematic review aimed to assess the effectiveness of GABA derivatives in the prevention of acute herpetic pain. The metaanalysis was conducted following the PRISMA guidelines using PICO format, registered in PROSPERO number CRD42018095758. PubMed, Web of Science, Ovid, Scopus, and EMBASE databases were searched. Records were included if they were randomized controlled trials of patients undergoing HZ infection, investigating the effect of GABA derivatives versus placebo in the treatment of HZ pain. Eligible trials were evaluated for the risk of bias. Then data were extracted and analysed. The number of patients with observed presence of pain after treatment was used to calculate odds ratio in a random effect model with the DerSimonian-Laird estimator. The I2 statistic was analysed for heterogeneity. The potential risk of bias was measured using Egger’s regression test. The meta-analysis included three randomized controlled trials with a total of 297 patients. The incidence of acute HZ pain events for GABA group was significantly lower compared to placebo group,18/148 vs 44/149, respectively (OR = 0.36; 95% CI = 0.14 to 0.93; Z = 2.11; P = 0.035), Egger’s test yielded P = 0.308. In conclusion, the present meta-analysis demonstrates that GABA derivatives reduce the incidence of acute herpetic pain. However, additional, well-designed randomized clinical trials are needed to determine their dose- and time-dependency regarding this symptom.

The effect of early and late pharmacological correction with GABA derivatives of psychoemotional state of offspring of rats with experimental preeclampsia

Introduction: Preeclampsia is a serious complication of pregnancy, which increases the risk of anxiety disorders and depression in children at different stages of ontogenesis. Materials and methods: The psychoemotional state of 70-day-old offspring of rats with experimental preeclampsia (EP) was studied after pharmacological correction from the 40th to 70th day of offspring life with GABA derivatives – succicard (22 mg/kg), salifen (7.5 mg/kg), phenibut (25 mg/kg) and comparison drug pantogam (50 mg) – in the Open field test, the Elevated plus maze test, and the Marble burying test. The above mentioned tests, together with the Porsolt test, were performed at the age of 18 months. At the second step, the offspring received succicard (44 mg/kg), salifen (15 mg/kg), phenibut (50 mg/kg) and pantogam (100 mg) from the 24th to 25th month of life. After that, the animals were tested. Results and discussion: The EP progeny had an increased level of anxiety and depression, as well as obsessive-compulsive disorder. Early GABA derivatives exposure limited anxiety and depression in the animals aged 70 days and 18 months, with salifen limiting compulsive behavior. Late GABA derivatives “treatment” exerted anti-compulsive and antidepressant effects, with phenibut having a greater degree of anxiolytic activity. Succicard, salifen and phenibut were comparable or superior to pantogam in terms of effectiveness. Conclusion: EP has a negative effect on the psychoemotional state of offspring. Early and late pharmacological correction with derivatives of GABA, such as succicard, salifen and phenibut, reduced anxiety, manifestations of obsessive-compulsive disorder, and depression in offspring of the rats with EP pregnancy.

Between Cognitivity and Neuropathies: Neuroimaging of the Effects of GABAergic Modulation of the Hippocampus and Prefrontal Neocortexis by Normalized Brain Electrograms

A comparative analysis conducted across the entire range of normalized brain electrograms (NBE) revealed the selective effect of gamma-aminobutyric acid (GABA) derivatives in the hippocampus and frontal pole of the neocortex. A signifi cant similarity in the level of activation of these brain regions was revealed under the action of glutamine and, particularly, gabapentin. For gabapentin, the activity of the hippocampus is more comparable to that in the anterior suprasilvius gyrus. Under the action of pregabalin, NBE revealed a similarity between the hippocampus and the proreal gyrus, with a more pronounced activity being registered in the range of 1–10 Hz. The NBE activity in the anterior suprasilvian gyrus was lower than that in the proreal gyrus. Under the action of phenibut, the activity of the hippocampus was higher than that of the prefrontal cortex across the 30–40 Hz range; however, under the action of aminalon, this phenomenon was observed for all the analysed rhythms. The predominant effect of GABA derivatives on the high-frequency components of the γ-rhythms of NBE was established. The most pronounced activation effects in γ-rhythms were characteristic of aminalon, while the most pronounced effects of deprimation were characteristic of gabapentin. The overall picture of the γ-rhythm activity was similar under the administration of glutamine, pregabalin and phenibut, as well as being generally close to the background level. The effects of glutamine and pregabalin in the analysis of NBE showed similarities across the frequency ranges of about 40–44 Hz and 60–64 Hz. The effects of pregabalin, gabapentin, and phenibut were similar across the frequency range of about 52–62 Hz. In the high-frequency γ-rhythms, gabapentin, pregabalin and phenibut were characterized by peaks in the range of 44–50 Hz, 40–55 Hz and 35–40 Hz, respectively. Aminalon showed no similarities with other GABA derivatives and was characterized by an extremum in the γ-rhythm at a frequency of about 41 Hz. Using instrumental methods for assessing cognitive behaviour and the mathematical analysis of NBE, the signifi cant role of the intercalary neurons (basket cells) of the hippocampus and prefrontal cortex in the implementation of glutamate and GABA effects was established. It was confi rmed that GABA derivatives function as the main mediator of intercalary neurons in the systemic activity of the brain. The maximum values of NBE under the action of all the GABA derivatives under study coincide with the pharmacodynamic and pharmacokinetic parameters of these drugs. A comparative analysis of the effects of glutamate and all the studied GABA derivatives revealed the greatest similarity of the former with phenibut. Aminalon, being a synthetic analogue of GABA, differs from all other drugs under study by the highest activation of the general level of NBE. The effects of neuroimaging refl ect the properties and nature of the effect of drugs on cognitive functions, intra-centre relations of the brain and higher nervous activity. New mechanisms of the systemic action of GABA derivatives were studied. The obtained results confi rm that the normalized electrographic activity of various parts of the brain can be used to identify certain physiological and pathogenetic mechanisms of the most important functions of the brain and their disorders. Activation of the GABAergic stress-limiting system can be considered as one of the promising methods for the selection of approaches to preventing and treating diseases associated with neurogenic and psychogenic factors.