Description

Agomelatine Nootropic Powder

 

 

 

CAS Number	138112-76-2
Other Names	Thymanax, Valdoxan, 138112-76-2, N-(2-(7-Methoxynaphthalen-1-yl)ethyl)acetamide, S20098, S-20098, Melitor, AGO-178, AGO 178, CHEMBL10878, UNII-137R1N49AD
IUPAC Name	N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
Molecular Formula	C₁₅H₁₇NO₂
Molecular Weight	243.3
Purity	≥99% Pure (LC-MS)
Liquid Availability	30mL liquid (25mg/mL, 750mg bottle)
Powder Availability	1 gram, 60 capsules (25mg/capsule, 1500mg bottle)
Gel Availability	N/A
Storage	Store in a dry, cool, dark place. For best preservation, store at 4°C or colder away from bright light.
Terms	All products are for laboratory developmental research USE ONLY. Products are not for human consumption.

 

What is Agomelatine?

Agomelatine is a nootropic compound with the potential to elicit antidepressant effects by acting as a melatonergic agonist for MT1 and MT2 receptors, as well as serotonergic antagonist for 5-HT2C receptors. Previous research has found that agomelatine improves symptoms of depression related to unpredictable stress by affecting the levels of brain-derived neurotrophic factor in the hippocampus [1].

 

Main Research Findings

1) Treatment with agomelatine was found to prevent comorbid depression by suppressing inflammatory signaling in a model of acquired epilepsy.

2) Treatment with agomelatine was found to have antidepressant effects on test subjects without eliciting any adverse effects on sexual behavior or development.

 

Selected Data

1) Previous research has found that depression is the most frequent psychiatric disorder that accompanies temporal lobe epilepsy. The research team of Tchekalarova et al examined the effects of treatment with the nootropic, agomelatine, on the symptoms of depression related to epilepsy. For the purpose of this study, adult male Wistar rats weighing 200-230 grams each were utilized. The test subjects were housed 3-4 to a cage and were maintained under standard laboratory conditions with free access to food and water. Status epilepticus was induced in the rats through an injection of kainate acid, following the injection the rats were kept in individual cages in order for the research team to monitor and record occurrences of spontaneous motor seizures through the use of 24 hour video recording and EEG monitoring [2].

Kainate acid was intraperitoneally injected at a dose of 5 mg/kg, followed by a half-dose of 2.5 mg/kg, 1 hour later. A modified Racine’s scale was used in order for the researchers to monitor the intensity of the seizures. Class I and class II partial seizures characterized by immobility, facial automatism, head nodding, and wet-dog shakes were not scored. Additional injections of kainate acid were based on the detection of class III seizures defined by forelimb clonus with lordotic posture, class IV seizures defined by rearing and continued forelimb clonus, and class V seizures defined by forelimb clonus and loss of posture. Seizure intensity determined whether a half-dose of kainate acid should be injected or whether administered should be discontinued. The onset of status epilepticus was characterized by the occurrence of >9 sustained motor seizures per hour; onset typically required between 3 and 4 doses of kainate acid [2].

After kainate acid-induction of status epilepticus, the animals were randomly divided into four different experimental treatment groups. Group 1 included control rats treated with the vehicle substance, hydroxyethyl cellulose; group 2 included control rats treated with agomelatine; group 3 included rats injected with kainate acid and treated with a hydroxyethyl cellulose; and group 4 included rats injected with kainate acid and treated with agomelatine. Agomelatine was intraperitoneally injected at a dose of 40 mg/kg dissolved in hydroxyethyl cellulose, 1 hour after status epilepticus was induced via kainate acid. After the first initial dose of the nootropic, all surviving test subjects included in the group administered both kainate acid and agomelatine continued treatment for 10 weeks receiving the same 40 mg/kg dose on a daily basis. It is important to mention that the neuroprotective effects of agomelatine was shown to be most potent within 1 hour of administration [2].

During the last 10 days of experimental treatment, 4 hours after the occurrence of a spontaneous motor seizure. The rats were subject to several different behavioral tests including the splash test, the sucrose preference test, the novelty-suppressed feeding test, and the forced swimming test. The splash test consisted of spraying 10% sucrose solution on the body of the rats in their home cage in order to dirty their coat and trigger grooming behavior. The research team observed and recorded the total amount of time spent grooming over a 5 minute period.

The next behavior test performed was the sucrose preference test that was performed by supplying each eat with two identical wattles with 100 mL of tap water on the first day of trials. The following day one of the bottles of tap water was replaced by 1% sucrose solution; the testing took place over 24 hours and the bottles were weighed after 12 hours. The research team calculated their taste preference as a percentage of volume of sucrose solution to the total volume of fluid, both water and sucrose solution, consumed over 12 hours [2].

The novelty-suppressed feeding test was performed next. To begin, the rats were food-deprived for 48 hours and were placed in the testing room 30 minutes before the actual testing took place. The trial took place between 10 AM and 12 PM under diffused light in a soundproof room and after the 30 minutes pre-trial period the rats were placed into the corner of the open field test apparatus. A circular white paper measuring 12 cm in diameter was placed in the center of the field and several chow pellets were placed on top of it. Two researchers recorded the latency to start feeding behavior and the test was stopped after the initiation of feeding or after 600 seconds with no activity had passed. After the traditional novelty-suppressed feeding test was performed modifications were made due to the increase of anxiety that is associated with suppression of feeding and the desire to approach food in a novel environment. Modifications included placing the rats in their home cage and placing pellets on the lid while the researchers recorded the latency to start eating [2].

The last behavioral test that took place was the forced swimming test where the rats were placed in a transparent plastic container filled up to 30 cm with water for 5 minutes. During this 5 minute period the research team recorded the time of immobility, defined as the movement only to maintain head above the surface of the water. Despair and hopeless behavior was indicated by the increase of immobility exhibited by the test subjects. A subset of the test subjects were euthanized 24 hours after the final injection of vehicle or agomelatine in order to assess levels of pro-inflammatory compounds, IL-1-beta and corticosterone. Trunk blood was collected and centrifuged for 10 minutes in order to separate the plasma that was stored for further analysis. IL-1-beta was measured using a Quantikine Elisa assay kit and corticosterone was measured using a corticosteroid Elisa assay kit [2].

2) The research team of Canpolat et al investigated the effects of agomelatine on sexual response and depressive behavior in male rats. For the purpose of this study, 21 day-old prepubertal Sprague-Dawley rats weighing 40+/- 2 grams were utilized. The animals were weaned from their mothers at 21 days and maintained under a reversed light/dark schedule at a constant temperature and humidity with free access to food and water. Valdoxan tablets containing 25 mg of agomelatine were crushed up everyday and dissolved in saline in order for 10 mg/kg of the nootropic to be administered orally everyday and 9 AM. Agomelatine was administered to the test subjects from day 21 to day 120 in male rats and day 90 in female rats while the control group received a daily 1 mg/kg oral dose of saline.Throughout treatment the daily food and water intake, as well as body weight gain of the animals were carefully monitored. Morphological signs of puberty in both male and female rats were evaluated from day 26 until they reached puberty. Female rats were euthanized after 90 days while males were maintained until 120 days before being euthanized [3].

Prior to euthanasia, sexual behavioral tests were performed between the hours of 1300 hours and 1600 hours in a dark room with a night vision camera system. The male rats were placed in a rectangular testing apparatus where they were allowed to habituate for 15 minutes, followed by the placement of a receptive female into the arena. The female rats were ovariectomized 3 weeks prior but were made sexually receptive through injection of 10 ug of estradiol benzoate dissolved in 0.2 ml of sesame oil 48 hours prior to testing, and 500 ug of progesterone dissolved in 0.2 ml of sesame oil 6 hours prior to testing. Each trial lasted 30 minutes while mount latency of the introduced female rate, intromission latency, ejaculation latency, ejaculation frequency, postejaculatory interval, mount latency prior to first ejaculation, intromission frequency, and copulatory efficiency were measured by the research team [3].

The forced swimming test is typically used to assess potential depressive behavior and antidepressant activity of various drugs. For the purpose of this study a modified version of the forced swimming test was used in order to observe the antidepressant effects of chronic treatment with agomelatine in comparison to treatment with a vehicle. Pretesting sessions began by individually placing the animals into plexiglass cylinders filled with 39 cm of water for 15 minutes. The rats were then removed, dried off, and returned to their cage so the cylinders could be emptied and cleaned. 24 hours after the first official trial of the modified forced swimming test occurred. Each trial was conducted for 4 minutes while a video camera mounted above the apparatus recorded the behavior of the animals while in the apparatus.

The forced swimming test assesses for behavioral despair, represented by the total duration of the animals’ immobile posture while in the water. When becoming immobile the rats float in an upright position only making small movements to keep their head above the water. Additionally, climbing behavior was observed as well and was characterized as struggling movements to get out of the cylinder with the animals’ forepaws placed above the surface of the water. Finally, swimming behavior was recorded and defined as primarily active horizontal swimming motions throughout the cylinder. After the forced swimming tests were completed, female rats were euthanized at day 90 and male rats were euthanized at day 120; blood samples were collected and reproductive organs were dissected and weighed for further analysis [3].

Sperm concentration in the right cauda epididymal tissue was examined using a haemocytometer, while the left cauda epididymal tissue was used to analyze sperm motility. A light microscope with a heated stage was then used to calculate the percentage of sperm motility. Levels of luteinizing hormones and follicle-stimulating hormones were measured in the serum by coating immunoplates with either hormone and transferring the samples to the plates after incubation with primary antibodies. The plates were then washed and the secondary antibody conjugated to streptavidin peroxidase was added into each well while color was developed using tetramethylbenzidine. The plates were read at an absorbance of 450 nm in order to detect levels of luteinizing hormone and follicle-stimulating hormone in the samples [3].

 

Discussion

1) Following injection of kainate acid, 4 out of 30 test subjects died from status epilepticus. All of the rats injected with kainate acid developed spontaneous motor seizures that were verified by the research team using video recording or EEG monitoring. The results reported that in comparison to rats injected with kainate acid and administered a vehicle compound, the rats treated with agomelatine experienced a significant decrease in the onset latency of spontaneous motor seizures, with the measured as 18.0 +/- 5.85 days and 9.8 +/- 2.05 days, respectively. However, between the rats administered kainate acid and either a vehicle compound or the active nootropic, there were no significant changes between the frequency of motor seizures or activity of epileptiform [2].

Figure 1: Changes in the frequency of seizures in response to injection with kainate acid and treatment with either a vehicle compound or agomelatine.

Once spontaneous motor seizures were observed in all test subjects 10 weeks after the induction of status epilepticus via kainate acid injection, the splash test was performed as an indicator for depression. Two-way ANOVA testing found that there was a significant effect between epilepsy and the treatment administered, suggesting that the anti-depressant effects of agomelatine were dependent on the epileptic condition of the test subjects. There was also decreased grooming behavior observed in the rats injected with kainate acid and treated with a vehicle compound. However, this depressive behavior was alleviated in the rats treated with agomelatine [2].

Figure 2: Changes across the experimental treatment groups in grooming behavior as an indicator of depression during the splash test.

ANOVA statistical analysis found that during the novelty-suppressed feeding test, the interaction between the delivered treatment and status epilepticus was indicative of the disease-modifying potential of agomelatine. An increased latency for feeding was observed in the rats injected with kainate acid and administered a vehicle compound, while agomelatine treatment was shown to significantly decrease latency to feed in the animals. With the modified version of the test the results reported that there was no significant difference in the latency to feed when the animals were tested in their home cage [2].

Figure 3: Changes across the experimental treatment groups in latency to eat during the novelty suppressed feeding test in B) a novel environment and C) the animals’ home cages.

In terms of the sucrose test, post hoc analysis found that there was no significant difference among the experimental treatment groups for preference for sucrose during the light phase of the day. However, during the dark phase, the animals injected with kainate acid and administered a vehicle compound saw a significant increase in phase-dependent depressive behavior in comparison to the control group of rats. Depressive behavior in epileptic rats during the dark phase was shown to be effectively prevented by chronic treatment with agomelatine. Finally, ANOVA analysis performed on the data collected from the forced swimming test revealed a significant effect between status epilepticus and the treatment administered, indicating that agomelatine is dependent on epilepsy in the animals. A post hoc test performed on the data found that the depressive behavior of epileptic rats was prevented by treatment with agomelatine [2].

Figure 4: Changes across the different experimental treatment groups in A) preference percentage for sucrose during the light phase, B) preference percentage for sucrose during the dark phase, and C) immobility time in seconds during the forced swimming test.

When assessing levels of pro-inflammatory compounds IL-1-beta and corticosterone, the performance of two-way ANOVA found that plasma levels of both IL-1-beta corticosterone were significantly affected by the interaction between status epilepticus and the treatment administered to the test subjects. Levels of pro-inflammatory cytokines increased considerably in the animals injected with kainate acid in comparison to the control group. However, treatment with agomelatine was found to suppress inflammatory signaling responses and reduce plasma levels of pro-inflammatory compounds in cases of status epilepticus [2].

Figure 5: Changes in the levels of pro-inflammatory compounds IL-1-beta and corticosterone in response to experimental treatments.

2) When looking at the effects of agomelatine on sexual behavior in male rats the results reported that there were no significant differences between the average number of ejaculations recorded in the control group versus the group treatment with agomelatine. However, treatment with agomelatine was also found to decrease the intromission frequencies in both the first and second test sessions that were completed on day 90 and day 105. Over the 30 minute testing period the total intromission frequency was also found to have significantly decreased during the first testing session, in the experimental group treated with agomelatine [3].

In terms of ejaculation latency there was no significant difference between treatment groups during the first session, however, there was a significant decrease in ejaculation latency during the second session in rats treated with agomelatine. Similar results were seen with copulatory efficiency, however, there was a significant decrease in the agomelatine treated group during session 1 while there were no noticeable changes during session 2. In terms of mount latency, intromission latency, postejaculatory intervals, and total copulatory efficiencies, there were no remarkable changes noted between treatment groups.

The results of the forced swimming test reported that administration of agomelatine led to a significant decrease in the duration of immobility while in the water. The rats treated with the nootropic were also found to spend more time swimming around the apparatus in comparison to the animals treated with a vehicle. There were no remarkable changes in the climbing time of the animals treated with agomelatine, however, the research noted that there was a trend in the results exhibiting a tendency for climbing times to be increased in the agomelatine treated animals [3].

Figure 6: Effects of treatment with agomelatine on swimming, climbing, and immobility exhibited by the test subjects during the forced swimming test.

Treatment with agomelatine in male rats was also found to significantly increase pubertal weight in comparison to the control group of rats, however the weight of the reproductive organs including the testicle, epididymis, seminal vesicle, and prostate gland, did not exhibit any noticeable changes. In comparison to the female rats, after administration of agomelatine pubertal weight was found to decrease in comparison to the control rats while both ovarian and uterine weight was shown to significantly increase in response to treatment with agomelatine. Levels of luteinizing hormone and follicle-stimulating hormone did not exhibit any remarkable changes in male or female rats. These findings allowed the research team to conclude that treatment with agomelatine elicits antidepressive effects without causing concurrent sexual and reproductive dysfunction [3].

Figure 7: Changes in pubertal weight of male rats in response to treatment with agomelatine.

Figure 8: Changes in pubertal weight of female rats in response to treatment with agomelatine.

Figure 9: Changes in the levels of luteinizing hormone and follicle stimulating hormone in male rats

Figure 10: Changes in the levels of luteinizing hormone and follicle stimulating hormone in female rats.

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Xu J, Zhu C, Jin P, Sun W, Yu E. Agomelatine prevented depression in the chronic restraint stress model through enhanced catalase activity and halted oxidative stress. PLoS One. 2024 Feb 9;19(2):e0289248. doi: 10.1371/journal.pone.0289248. PMID: 38335199; PMCID: PMC10857580.

[2] Tchekalarova J, Atanasova D, Kortenska L, Atanasova M, Lazarov N. Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling. Neurobiol Dis. 2018 Jul;115:127-144. doi: 10.1016/j.nbd.2018.04.005. Epub 2018 Apr 10. PMID: 29653194.

[3] Canpolat S, Ulker N, Yardimci A, Bulmus O, Ozdemir G, Sahin Z, Ercan Z, Serhatlioglu I, Kacar E, Ozcan M, Turk G, Ozkan Y, Atmaca M, Yilmaz B, Kelestimur H. Studies on the reproductive effects of chronic treatment with agomelatine in the rat. Eur J Pharmacol. 2016 Jan 5;770:33-9. doi: 10.1016/j.ejphar.2015.11.054. Epub 2015 Nov 28. PMID: 26643170.

Characteristics of Agomelatine

Agomelatine is a unique antidepressant that has been shown to increase melatonin activity by mimicking the effects of melatonin at the receptor target sites. Melatonin is commonly known as the “sleep hormone” as it affects circadian rhythm and sleep-phase cycles. Important research has concluded that there is a direct link between lack of sleep and depression. That being said, disruption of sleep is considered one of the most prevalent signs of a depressive illness. In animal models, depressed subjects typically exhibit decreases in total sleep time and sleep efficiency, difficulty falling asleep, early wake times, and abnormal instances of rapid eye movement (REM).

Further research solidifies this claim, suggesting that subjects with major depressive order (MDD) or seasonal affective disorder (SAD) have also experienced disruptions in amplitude and rhythm of melatonin secretions as well as circadian rhythm. Because agomelatine has shown promise in treating depression while manipulating melatonin activity, important research is currently being conducted to attempt to understand the mechanism of action of agomelatine (https://pubmed.ncbi.nlm.nih.gov/19454302/).

The compound is considered to be an analog of melatonin due its categorization as an acetamide naphthalene. Research has found that the compound acts as a melatonin agonist with affinity for receptors MT1, MT2, and an antagonist for the 5HT2C (serotonergic) receptor. It’s important to mention that agomelatine acts as a 5HT2C receptor antagonist, considering that activation of this receptor leads to inhibited release of dopamine and norepinephrine. By inhibiting activation of this receptor, agomelatine actually leads to increased levels of norepinephrine and dopamine, explaining its mechanism of action as an antidepressant.

Agomelatine is typically administered orally and is metabolized in the liver by isoenzymes 1A2 and 2C9, as well as cytochrome P450. It’s interesting to note that recent studies have shown that when administering agomelatine in combination with compounds that inhibit the 1A2 isoenzyme pathway, total agomelatine plasma levels increase. Additionally, when compounds that induce activation of the 1A2 isoenzyme platforms are administered, agomelatine plasma levels decrease (https://pubmed.ncbi.nlm.nih.gov/11102739/).

 

Antidepressant Effects of Agomelatine

Through the use of animal models, researchers have been able to further examine the link between agomelatine’s antidepressant effects and its ability to increase melatonin activity. Because the compound is considered a melatonin agonist, administration of agomelatine typically leads to elicited effects similar to melatonin. For example, studies have found that, like melatonin, agomelatine is able to resynchronize circadian rhythms in animals with induced delayed sleep-phase syndrome. However, unlike melatonin, agomelatine exhibits anxiolytic and antidepressant qualities. Research conducted by Millan et. Al examined the extent of which the anxiolytic effects were expressed in rats. The results reported that when comparing agomelatine to benzodiazepine, clorazepate, and the 5HT2 receptor antagonist, SB243,213, agomelatine yielded the best performance results in tests meant to measure anxiolytic activity.

Many significant studies have found that administration of agomelatine improves performance in terms of measured models of depressions. A study conducted by researchers Bourin et. Al observed the efficacy of agomelatine in treating depression against compounds such as melatonin, fluoxetine, and imipramine. Measuring depression throughout the animal model was based on how the rats performed on a forced swim test (FST). In doses of 4, 16, and 32 mg/kg per day, agomelatine was able to significantly improve FST performance by decreasing immobility duration. This indicates that agomelatine is able to act as an efficient antidepressant in terms of an animal model FST (https://pubmed.ncbi.nlm.nih.gov/15069466/).

A similar study conducted by Norman et. Al assessed the antidepressant effects of agomelatine by measuring depression through locomotor hyperactivity in olfactory bulbectomy rats. Doses of 10 and 50 mg/kg per day of agomelatine were given to male Sprague-Dawley rats over an experimental period of 14 days. Compared to the other compounds administered, both the 10 and 50 mg/kg doses drastically decreased cases of locomotor hyperactivity. This significant reduction in measured behavior supports the claim that agomelatine is an effective antidepressant in this model. It should be noted that administration of melatonin alone led to no significant change in the measurement of either of the previously mentioned models, as it caused no change in the activity of 5HT receptors or the secretion of noradrenaline (https://pubmed.ncbi.nlm.nih.gov/22040921/).

The nootropics sold by Umbrella Labs are sold for laboratory research only. The description above is not medical advice and is for informative purposes only.

Agomelatine is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering.

 

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