Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Effects of acute administration of 4-allyl-2,6-dimethoxyphenol in mouse models of seizures.

Epilepsy, a chronic neurological disorder characterized by recurrent unprovoked seizures, presents a substantial challenge in approximately one-third of cases exhibiting resistance to conventional pharmacological treatments. This study investigated the effect of 4-allyl-2,6-dimethoxyphenol, a phenolic compound derived from various natural sources, in different models of induced seizures and its impact on animal electroencephalographic (EEG) recordings. Adult male Swiss albino mice were pre-treated (i.p.) with a dose curve of 4-allyl-2,6-dimethoxyphenol (50, 100, or 200 mg/kg), its vehicle (Tween), or standard antiepileptic drug (Diazepam; or Phenytoin). Subsequently, the mice were subjected to different seizure-inducing models - pentylenetetrazole (PTZ), 3-mercaptopropionic acid (3-MPA), pilocarpine (PILO), or maximal electroshock seizure (MES). EEG analysis was performed on other animals surgically implanted with electrodes to evaluate brain activity. Significant results revealed that animals treated with 4-allyl-2,6-dimethoxyphenol exhibited increased latency to the first myoclonic jerk in the PTZ and PILO models; prolonged latency to the first tonic-clonic seizure in the PTZ, 3-MPA, and PILO models; reduced total duration of tonic-clonic seizures in the PTZ and PILO models; decreased intensity of convulsive seizures in the PTZ and 3-MPA models; and diminished mortality in the 3-MPA, PILO, and MES models. EEG analysis indicated an increase in the percentage of total power attributed to beta waves following 4-allyl-2,6-dimethoxyphenol administration. Notably, the substance protected from behavioral and electrographic seizures in the PTZ model, preventing increases in the average amplitude of recording signals while also inducing an increase in the participation of theta and gamma waves. These findings suggest promising outcomes for the tested phenolic compound across diverse pre-clinical seizure models, highlighting the need for further comprehensive studies to elucidate its underlying mechanisms and validate its clinical relevance in epilepsy management.

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study

Abstract This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Extra virgin coconut oil (Cocos nucifera L.) intake shows neurobehavioural and intestinal health effects in obesity-induced rats.

The present study aimed to evaluate the effect of E-VCO on the neurobehaviour and intestinal health parameters of obesity-induced rats, focusing on food consumption, body composition, bacterial and faecal organic acids and histological analyses in the hippocampus and colon. A total of 32 male Wistar rats were randomized into healthy (HG, n = 16) and obese groups (OG, n = 16), which consumed a control or cafeteria diet for eight weeks, respectively. After this period, they were subdivided into four groups: healthy (HG, n = 8); healthy treated with E-VCO (HGCO, n = 8); obese (OG, n = 8); obese treated with E-VCO (OGCO, n = 8), continuing for another eight weeks with their respective diets. The treated groups received 3000 mg kg-1 of E-VCO and control groups received water via gavage. Food preference, body weight gain, body composition, anxiety- and depression-like behaviour were evaluated. Bacteria and organic acids were evaluated in faeces, and histological analyses of the hippocampus and M1 and M2 macrophages in the colon were performed. E-VCO reduced energy intake (16.68%) and body weight gain (16%), although it did not reduce the fat mass of obese rats. E-VCO showed an antidepressant effect, increased lactic acid bacteria counts and modulated organic acids in obese rats. Furthermore, E-VCO protected the hippocampus from neuronal degeneration caused by the obesogenic diet, decreased the M1 macrophage and increased the M2 macrophage population in the gut. The results suggest neurobehavioural modulation and improved gut health by E-VCO, with promising effects against obesity-related comorbidities.

Orofacial antinociceptive effects of perillyl alcohol associated with codeine and its possible modes of action.

This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Orofacial antinociceptive effects of perillyl alcohol associated with codeine and its possible modes of action

Abstract This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Does intermittent fasting associated with aerobic training influence parameters related to the gut-brain axis of Wistar rats?

BACKGROUND: Intermittent fasting (IF) and aerobic training have demonstrated beneficial effects on intestinal microbiota composition, but little is known about benefits to the brain through the gut-brain axis. The present study aimed to evaluate gut-brain axis parameters in Wistar rats submitted to IF associated or not with aerobic training. METHODS: Male rats were evaluated for training performance and then randomized into 4 groups of ten: sedentary control (SC), trained control (TC), sedentary intermittent fasting (SIF), and trained intermittent fasting (TIF), and evaluated during four weeks. RESULTS: The adiposity index was similar among the TC (2.15±0.43%), SIF (1.98±0.69%) and TIF (1.86±0.51%) groups, and differed from SC (2.98±0.80%). TIF had lower counts of lactic acid bacteria, while SIF had higher counts of Bifidobacterium and Enterococcus. TIF had the highest amount of formic acid in faeces (44.44±2.40 µmol/g) and lowest amount of succinic acid in the gut (0.38±0.00 µmol/g), while SIF had the highest propionic acid amount in the faeces (802.80±00.33 µmol/g) and the lowest amount of lactic acid in the gut (0.85±0.00 µmol/g). TIF demonstrated a tendency towards an anxiolytic effect and SIF showed potential antidepressant effect. IF caused different brain and intestinal injuries. TIF rats presented a diffuse and intense marking of IL-1ß in the hippocampus. CONCLUSION: IF and aerobic exercise, associated or not, can modulate parameters related to the gut-brain axis of Wistar rats, and some benefits may be related to the amounts of organic acids.

Mucuna pruriens Administration Minimizes Neuroinflammation and Shows Anxiolytic, Antidepressant and Slimming Effects in Obese Rats.

This study evaluated the effect of Mucuna pruriens (MP) administration on neuroinflammation and behavioral and murinometric parameters in obese rats. Proximate composition, oligosaccharide and phenolic compound profile of MP were determined. Wistar adult male rats were randomized into healthy (HG) and obese group (OG). The HG consumed a control chow diet while OG consumed a cafeteria diet for eight weeks. Then, they were subdivided into: Healthy (HG); Healthy with MP administration (HGMP); Obese (OG); Obese with MP administration (OGMP), with the consumption of the respective diets remaining for another eight weeks, in addition to gavage with MP extract to supplemented groups (750 mg/kg weight). MP presented a composition rich in proteins and phenolic compounds, especially catechin, in addition to 1-kestose and levodopa. Supplementation reduced food intake, body weight, and thoracic and abdominal circumferences in obese rats. MP showed anxiolytic and antidepressant effects and reduced morphological damage and expression of interleukin 6 in the hippocampus of obese rats. MP treatment showed satietogenic, slimming, anxiolytic and antidepressant effects, besides to minimizing hippocampal neuroinflammation in obese rats. Our results demonstrated the potential anti-obesity of MP which are probably related to the high content of bioactive compounds present in this plant extract.

CA1 inactivation impairs episodic-like memory in rats.

Episodic memory was initially believed to be unique to humans. However, studies demonstrate that nonhuman species discriminate items based on the triad what, where and when. Here we addressed the role of the dorsal hippocampal subfield CA1 in an integrative what-where-when task in Wistar rats. We performed bilateral inactivation of dorsal CA1 with the GABAA agonist muscimol previously to the task. As expected, sham-operated animals recollected an integrative memory for objects (what), their places (where) and temporal order (when). However, the inactivation of CA1 impaired the performance of the three components of episodic-like memory. In addition, total time of objects exploration and distance traveled were not different between groups, indicating that rats had similar levels of motivation, thus, alterations in exploration does not account for impaired locomotor performance. Altogether, our data provides evidence that CA1 plays an important role in episodic-like memory.

Anxiolytic-like effects and mechanism of (-)-myrtenol: a monoterpene alcohol.

The essential oil of Myrtus communis L. (Myrtaceae) and its compounds have been popularly used in numerous health disorders, including insomnia and nervous conditions, but their effects on central nervous system (CNS) have not been explored yet. We evaluated the anxiolytic-like effects and possible action mechanism of (-)-myrtenol (MYR), a monoterpenoid alcohol present in essential oil of M. communis L. Animal models of elevated plus maze (EPM), light-dark transition (LDT), open field and rotarod tests were used in the present study. MYR was administered in male rats. Diazepam was used as the standard drug (positive control) and flumazenil was used to elucidate the possible action mechanism. The results showed that none of the doses of MYR had effect on the resistance time in rotating bar, but caused reduction in the number of falls in rotarod tests when compared with a negative control. Similarly, MYR had no effect on the number of crossings, groomings or rearings in open field tests when compared with a negative control. However, in EPM and LDT tests, MYR significantly increased (p<0.001) the number of entries in open arms (F7,49=9.867), the time spent in open arms (F7,49=53.97) and the time spent in light compartment (F7,56=27.38), when compared with negative and positive controls, respectively. Flumazenil was able to reverse the effects of diazepam and MYR. These results suggest that MYR presents anxiolytic-like activity and that effect can be mediated by GABAergic transmission.

Central nervous system effects of Dioclea grandiflora pods on mice / Efectos en el sistema nervioso central de la vaina de Dioclea grandiflora en camundongos

Many plant substances are known for their interference with the central nervous system (CNS). Dioclea grandiflora Mart. Ex. Benth (Fabaceae) is a plant used in folk medicine to treat prostate disorders and kidney stones whose extracts from its seeds and root barks were reported to have a significant activity on the CNS and analgesic effect in rodents. In this study, the psychopharmacological activities of D. grandiflora were investigated, using the pods of this plant. Swiss mice were submitted to acute treatments with ethanol extract from the pods of D. grandiflora (EDgP) at doses of 75, 150 and 300 mg/kg by intraperitoneal administration followed by the evaluation of anxiety, depressant and anticonvulsant-related responses. The treatment with EDgP produced a depressant activity on the CNS and a sedative effect in mice. These findings suggest that EDgP has a central activity in mice, indicating an anxiogenic effect.

Varias sustancias de plantas son conocidas por su acción en el sistema nervioso central (SNC). La Dioclea grandiflora Mart. Ex. Benth (Fabaceae) es una planta utilizada en la medicina popular para tratar enfermedades en la próstata y piedras en los riñones, cuyos extractos de sus semillas y de las cáscaras de sus raíces presentan una actividad significativa sobre el SNC y efecto analgésico en roedores. En este estudio, las actividades psicofarmacológicas de D. grandiflora fueron investigadas, utilizando la vaina de la planta. Camudongos Swiss fueron sometidos a tratamientos agudos por la administración intraperitoneal del extracto etanólico de la vaina de D. grandiflora (EDgP) en dosis de 75, 150 y 300 mg/kg administrados intraperitonealmente seguida por la evaluación de respuestas relacionadas con la ansiedad, depresión y anticonvulsivo. El tratamiento con EDgP produjo una actividad depresora sobre el sistema nervioso central y un efecto sedante en camundongos. Estos resultados sugieren que EDgP tiene una actividad central en camundongos, indicando un efecto ansiogénico.