Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence.

Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.

Effect of dietary supplementation with Lactobacillus helveticus R0052 on seizure thresholds and antiseizure potency of sodium valproate in mice.

OBJECTIVE: Both animal and human studies, though limited, showed that multi-strain probiotic supplementation may reduce the number of seizures and/or seizure severity. Here, we evaluated the effect of a single strain probiotic supplementation on seizure susceptibility, antiseizure efficacy of sodium valproate, and several behavioral parameters in mice. METHODS: Lactobacillus helveticus R0052 was given orally for 28 days. Its influence on seizure thresholds was evaluated in the ivPTZ- and electrically-induced seizure tests. The effect on the antiseizure potency of valproate was assessed in the scPTZ test. We also investigated the effects of probiotic supplementation on anxiety-related behavior (in the elevated plus maze and light/dark box tests), motor coordination (in the accelerating rotarod test), neuromuscular strength (in the grip-strength test), and spontaneous locomotor activity. Serum and brain concentrations of valproate as well as cecal contents of SCFAs and lactate were determined using HPLC method. RESULTS: L. helveticus R0052 significantly increased the threshold for the 6 Hz-induced psychomotor seizure. There was also a slight increase in the threshold for myoclonic and clonic seizure in the ivPTZ test. L. helveticus R0052 did not affect the threshold for tonic seizures both in the maximal electroshock- and ivPTZ-induced seizure tests. No changes in the antiseizure potency of valproate against the PTZ-induced seizures were reported. Interestingly, L. helveticus R0052 increased valproate concentration in serum, but not in the brain. Moreover, L. helveticus R0052 did not produce any significant effects on anxiety-related behavior, motor coordination, neuromuscular strength, and locomotor activity. L. helveticus R0052 supplementation resulted in increased concentrations of total SCFAs, acetate, and butyrate. CONCLUSIONS: Altogether, this study shows that a single-strain probiotic - L. helveticus R0052 may decrease seizure susceptibility and this effect can be mediated, at least in part, by increased production of SCFAs. In addition, L. helveticus R0052 may affect bioavailability of valproate, which warrants further investigations.

Neuroprotective Effects of Coffee Bioactive Compounds: A Review.

Coffee is one of the most widely consumed beverages worldwide. It is usually identified as a stimulant because of a high content of caffeine. However, caffeine is not the only coffee bioactive component. The coffee beverage is in fact a mixture of a number of bioactive compounds such as polyphenols, especially chlorogenic acids (in green beans) and caffeic acid (in roasted coffee beans), alkaloids (caffeine and trigonelline), and the diterpenes (cafestol and kahweol). Extensive research shows that coffee consumption appears to have beneficial effects on human health. Regular coffee intake may protect from many chronic disorders, including cardiovascular disease, type 2 diabetes, obesity, and some types of cancer. Importantly, coffee consumption seems to be also correlated with a decreased risk of developing some neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and dementia. Regular coffee intake may also reduce the risk of stroke. The mechanism underlying these effects is, however, still poorly understood. This review summarizes the current knowledge on the neuroprotective potential of the main bioactive coffee components, i.e., caffeine, chlorogenic acid, caffeic acid, trigonelline, kahweol, and cafestol. Data from both in vitro and in vivo preclinical experiments, including their potential therapeutic applications, are reviewed and discussed. Epidemiological studies and clinical reports on this matter are also described. Moreover, potential molecular mechanism(s) by which coffee bioactive components may provide neuroprotection are reviewed.

Salvinorin A Does Not Affect Seizure Threshold in Mice.

The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.

Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice.

Ursolic acid (UA) is a plant derived compound which is also a component of the standard human diet. It possesses a wide range of pharmacological properties, i.e., antioxidant, anti-inflammatory, antimicrobial and antitumor, which have been used in folk medicine for centuries. Moreover, influence of UA on central nervous system-related processes, i.e., pain, anxiety and depression, was proved in experimental studies. UA also revealed anticonvulsant properties in animal models of epilepsy and seizures. The aim of the present study was to investigate the influence of UA on seizure thresholds in three acute seizure models in mice, i.e., the 6 Hz-induced psychomotor seizure threshold test, the maximal electroshock threshold (MEST) test and the timed intravenous pentylenetetrazole (iv PTZ) infusion test. We also examined its effect on the muscular strength (assessed in the grip strength test) and motor coordination (estimated in the chimney test) in mice. UA at doses of 50 and 100 mg/kg significantly increased the seizure thresholds in the 6 Hz and MEST tests. The studied compound did not influence the seizure thresholds in the iv PTZ test. Moreover, UA did not affect the motor coordination and muscular strength in mice. UA displays only a weak anticonvulsant potential which is dependent on the used seizure model.

Evaluation of the Anticonvulsant Effect of Brilliant Blue G, a Selective P2X7 Receptor Antagonist, in the iv PTZ-, Maximal Electroshock-, and 6 Hz-Induced Seizure Tests in Mice.

Epilepsy is one of the most common neurological disorders which is diagnosed in around 65 million people worldwide. Clinically available antiepileptic drugs fail to control epileptic activity in about 30% of patients and they are merely symptomatic treatments and cannot cure or prevent epilepsy. There remains a need for searching new therapeutic strategies for epileptic disorders. The P2X7 receptor has been recently investigated as a new target in epilepsy treatment. Preclinical studies revealed that P2X7 receptor antagonists have anticonvulsant properties in some models of epilepsy. We aimed to investigate whether P2X7 receptor antagonist-brilliant blue G (BBG)-is able to change seizure threshold in three acute seizure models in mice, i.e., in the intravenous pentylenetetrazole seizure threshold, maximal electroshock seizure threshold and 6 Hz psychomotor seizure threshold tests. BBG was administered acutely (50-200 mg/kg, 30 min before the tests) and sub-chronically (25-100 mg/kg, once daily for seven consecutive days). Moreover, the chimney and grip strength tests were used to estimate the influence of BBG on the motor coordination and muscular strength in mice, respectively. Our results revealed only a week anticonvulsant potential of the studied P2X7 receptor antagonist because it showed anticonvulsant action only in the 6 Hz seizure test, both after acute and sub-chronic administration. BBG did not significantly influence seizure thresholds in the remaining tests. Motor coordination and muscular strength were not affected by the studied P2X7 receptor antagonist. In summary, BBG does not possess any remarkable anticonvulsant potential in acute seizure models in mice.

Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice.

Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10-200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg/kg. In conclusion, since sulforaphane was proconvulsant at a toxic dose, the safety profile and the risk-to-benefit ratio of sulforaphane usage in epileptic patients should be further evaluated.

Neuropharmacological characterization of the oneirogenic Mexican plant Calea zacatechichi aqueous extract in mice.

This study evaluates the neuropharmacological effects of the aqueous extract of the Mexican plant Calea zacatechichi Schltdl., which is commonly used in folk medicine to treat cough, asthma, and gastrointestinal disorders. Moreover, it has been used for centuries in traditional rituals based on divination and is thought to possess hallucinogenic activity. To test the neuropharmacological effects of the aqueous extract of C. zacatechichi we used mouse models of convulsions, an elevated plus-maze test and measured locomotor activity. We also evaluated the effect of the extract on antidepressant-like behavior in forced swim test, as well as on muscular strength in a grip test. Moreover the antinociceptive action of the extract was evaluated in the hot-plate and writhing tests. The chemical composition of the extract was evaluated using LC-MS techniques. The aqueous extract of C. zacatechichi did not affect any of the parameters measured in seizure models. It had also no influence on anxiety, exploratory behavior and muscular strength in the applied doses. On the other hand, the extract exhibited antinociceptive effect in the mouse model of abdominal pain. Chemical characterization of the extract showed the presence of chlorogenic acid, acacetin, and germacranolides. Based on this report we suggest that aqueous extract of C. zacatechichi has insignificant neuropharmacological effects in vivo and reduces abdominal pain perception. Our results, together with previous studies showing beneficial effects of the extracts obtained from C. zacatechichi suggest that these preparations may be used to treat medical conditions.

Evaluation of Anticonvulsant, Antidepressant-, and Anxiolytic-like Effects of an Aqueous Extract from Cultured Mycelia of the Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Higher Basidiomycetes) in Mice.

Ganoderma lucidum is a well-known medicinal mushroom with a long history of use. This study was designed to assess the anticonvulsant potential of an aqueous extract from cultured G. lucidum mycelium in 3 acute seizure models: timed intravenous pentylenetetrazole infusion, maximal electroshock seizure threshold, and 6-Hz-induced psychomotor seizure tests in mice. Moreover, antidepressant-like and anxiolytic-like effects of G. lucidum were evaluated using the forced swim test and the elevated plus maze test in mice, respectively. No changes in seizure thresholds in the intravenous pentylenetetrazole and maximal electroshock seizure threshold tests after acute treatment with G. lucidum extract (200-600 mg/kg) was observed. However, the studied extract (100-400 mg/kg) significantly increased the threshold for psychomotor seizures in the 6-Hz seizure test. In the forced swim test, G. lucidum (100-400 mg/kg) significantly reduced the duration of immobility. No anxiolytic-like or sedative effects were reported in mice pretreated with the extract (400-600 mg/kg). G. lucidum extract (50-2400 mg/kg) did not produce toxic effects in the chimney test (motor coordination) or grip-strength test (neuromuscular strength). Further studies are required to explain the neuropharmacological effects of G. lucidum and to identify its active ingredients that may affect seizure threshold, mood, or anxiety.

Role of the adenosine system and glucose restriction in the acute anticonvulsant effect of caprylic acid in the 6 Hz psychomotor seizure test in mice.

Although several studies have reported the acute anticonvulsant activity of caprylic acid in animal seizure models, little is known about the mechanism underlying this effect. Recently, the role of adenosine in the efficacy of the ketogenic diet has been postulated. Therefore, the present study aimed to evaluate the possible involvement of the adenosine system (in non-fasted mice) as well as the role of glucose restriction (in fasted and non-fasted mice) in the acute anticonvulsant activity of caprylic acid in the 6 Hz psychomotor seizure threshold test. We showed that the anticonvulsant effect of caprylic acid (30 mmol/kg, p.o.) was reversed by a selective adenosine A1 receptor antagonist (DPCPX, 1mg/kg, i.p.) and a selective adenosine A2A receptor antagonist (KW-6002, 1 mg/kg, p.o.) but not by glibenclamide (1 pg/mouse, i.c.v.) - the ATP-sensitive potassium (KATP) channel blocker. Co-administration of an ineffective dose of caprylic acid (20 mmol/kg) with an ineffective dose of adenosine transporter inhibitor (dipyridamole, 50 mg/kg, i.p.) significantly raised the threshold for the 6 Hz-induced seizures. A high dose of glucose (2 g/kg) significantly only diminished the anticonvulsant effect of caprylic acid (30 mmol/kg) in non-fasted mice, and this was accompanied by an increase in blood glucose level and no changes in ketone body level as compared to the caprylic acid-treated group. In both fasted and non-fasted mice treated with glucose and caprylic acid, a significant decrease in trunk blood pH occurred as compared to the control group. No alternations in motor coordination or muscular strength were noted with any drug treatment, apart from the caprylic acid and glibenclamide combination, where a significant decrease in the muscle strength was observed. The present study provides a new insight into the role of the adenosine system and low glucose usage in the mechanisms underlying the anticonvulsant effects of caprylic acid in the 6 Hz seizure test.

Effect of quercetin and rutin in some acute seizure models in mice.

Quercetin is one of the most widely occurring flavonoid which is also often present in plants as glycosidic form - rutin. These compounds are ingredients of plant diet and are also present in numerous pharmaceutical preparations and diet supplements which are taken by patients suffering from epilepsy and treating with antiepileptic drugs (AEDs). Influence of these compounds on central nervous system-related effects was proved both in experimental and clinical studies. Their influence on anxiety, depression, memory processes and convulsant activity was reported. The aim of the present study was to investigate the effect of quercetin and rutin in some models of seizures, i.e., in the model of psychomotor seizures induced by 6Hz stimulation, in the maximal electroshock seizure threshold and intravenous pentylenetetrazole tests in mice. We also examined a possible mechanism of anticonvulsant activity of quercetin and its influence on action of two AEDs, i.e., valproic acid and levetiracetam, in the 6Hz seizure test. Our results revealed only a weak anticonvulsant potential of the studied flavonoids because they showed anticonvulsant action at doses from 10 to 200mg/kg only in the 6Hz test and did not change seizure thresholds in the remaining tests. Moreover, anticonvulsant action of the studied flavonoids was short-term, noted only at pretreatment time ranging between 30 and 60min. The highest anticonvulsant activity of quercetin was correlated with its high plasma and brain concentration, which was revealed in a pharmacokinetic study. We did not note changes in the anticonvulsant action of the used AEDs combined with quercetin in the model of psychomotor seizures in mice. Neither quercetin and rutin nor combinations of quercetin with the studied AEDs produced any significant impairments of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test) and long-term memory (evaluated in the passive avoidance test) in mice. The results of the present study suggest that quercetin and rutin have only weak and short-term anticonvulsant potential. These flavonoids seem to be safe for patients with epilepsy because they neither changed activity of the studied AEDs nor produced any adverse effects.

Effects of sarcosine, a glycine transporter type 1 inhibitor, in two mouse seizure models.

Sarcosine, a natural amino acid found in muscles and other body tissues, is an endogenous glycine transporter type 1 inhibitor that increases the glycine concentration, resulting in an indirect potentiation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Sarcosine, similar to other NMDA receptor-activating agents, is an effective adjuvant in the treatment of schizophrenia. It is widely accepted that increased glutamatergic neurotransmission is involved in the initiation and propagation of seizures. Because sarcosine facilitates NMDA receptor function, it may affect the seizure threshold. Therefore, we examined the effects of sarcosine on the seizure threshold in two different mouse seizure models: the timed intravenous (iv) pentylenetetrazole (PTZ) infusion test and the maximal electroshock seizure threshold test. In the iv PTZ test, sarcosine did not exert a significant effect on the seizure threshold at any of the doses tested (100, 200, 400 and 800 mg/kg, ip). However, at doses of 400 and 800 mg/kg, sarcosine significantly raised the threshold for electroconvulsions (p < 0.01). The present findings indicate that sarcosine did not lower the seizure threshold. Conversely, sarcosine showed weak anticonvulsant properties by increasing the threshold current for the induction of tonic seizures. Therefore, sarcosine may be considered as a safe adjuvant treatment for schizophrenia without proconvulsant risk. In addition, the compound may serve as an interesting addition to epilepsy treatment.