IDRA-21 30ML LIQUID (10MG/ML, 300MG BOTTLE)

Main Research Findings

1) The study revealed that IDRA 21 has the potential to reduce pharmacologically induced cognitive impairments.

2) IDRA 21 was found to enhance cognition by attenuating the rapid auto desensitization of AMPA receptors.

 

Selected Data

1) The research team of Thompson et al examined the effects of IDRA 21 on cognitive impairments pharmacologically induced in patas monkeys. For the purpose of this study, two female and two male patas monkeys acted as test subjects. Each subject had experience with the behavioral procedures used, and had previous exposure to reversible experimental drugs. That being said the subjects were drug free for at least 2 weeks prior to the start of the study. Water was continuously available to all of the test subjects and the animals were maintained at approximately 90% of their free-feeding weight through a diet of banana-flavored food pellets, monkey chow, and various fruit and vitamin supplementation [2].

The monkeys were treated with both Alprazolam and IDRA 21. Alprazolam was administered orally, twice a week in doses ranging from 0.01 to 0.32 mg/kg. The oral solution was prepared by suspending the compound in a 5% solution of 2-hydroxypropyl-beta-cyclodextrin, mixed with 15 mL of fruit punch that the subject drank every Tuesday and Friday. The monkeys were then pretreated with a racemic mixture of IDRA 21 in doses ranging from 0.3 to 5.6 mg/kg. The nootropic was suspended in Tween80 and given to the subjects in the same manner as alprazolam. Each treatment was tested alone and in combination with each other with exposure to IDRA 21 lasting for 120 minutes and alprazolam exposure lasting for 60 minutes. Additionally, 1 to 30 mg/kg of aniracetam was administered to the subjects for direct comparison to IDRA 21. Each subject was housed in a standard, primate specific individual cage that was equipped with response panels to track activity during the behavioral testing. The acquisition component of the test began with the projection of one of four geometric forms onto a red background on three different response keys [2].

The goal of the test was for the animal to learn a four-response chain by pressing the correct key in the presence of each form. The forms include: a horizontal line, left correct, triangle, right correct, vertical line, center correct, circle, and right correct. Once the four-response chain was completed the lights turned off and a pilot lamp near the pellet dispenser was illuminated. The chain was reset once the pilot light was pressed and a fixed-ratio was set in place that scheduled food presentation after every fifth completion of the chain and pressing of the pilot lamp in order to maintain the four-response chain. In comparison, when one of the test subjects pressed an incorrect key there was a 5-second time out where the keys were dark and all responses were ineffective. That being said, an error did not reset the chain and the stimulus remained the same as before the 5-second time out. During the acquisition phase, the four-response chains were changed from session to session and each chain was selected to be equal in several ways.

During the performance component of the behavioral test, the four geometric forms were projected onto a green background while the left-center-left-right pattern of four-response chain remained the same across sessions. In all other aspects, the procedures of the performance component of the behavioral test were identical to those of the acquisition component of the behavioral test. Sessions were conducted on a daily basis. Each trial started with an acquisition period following the procedures outlined above, followed by a performance component. The subjects were advanced to the performance component after 10 food production reinforcements or after 15 minutes. Each session was terminated after 2 hours or after 60 reinforcements for females and 100 reinforcements for males were achieved [2].

2) In order to assess the effects of IDRA on cognitive functioning, the research team of Zivkovic et al utilized male Sprague-Dawley rats weighing 250-300 grams. The animals were housed three to a cage and maintained under standard laboratory conditions for at least four days prior to undergoing various behavioral studies. Solutions of NBQX, scopolamine, and alprazolam were prepared and intraperitoneally injected in a volume of 0.5 ml. Both the water maze and the passive avoidance experiments were performed 15 minutes after the injection of NBQX and 20 minutes after the injection of alprazolam and scopolamine. 2 ml of IDRA 21 and aniracetam were then administered to the rats through an oral gavage, 1 hour before testing took place. Prior to oral administration of the nootropics or a vehicle compound, the rats fasted for 6 hours [3].

The first behavioral test was the water maze experiment. The apparatus was a black fiberglass, cylindrical tank filled with room temperature water with opaque plastic walls arranged as three concentric squares and removable doorways inside of the pool. The doors are opened and closed to create a variety of mazes with incorrect options that the rats must remember in order to choose the shortest swimming path from the central compartment to the exit platform. The maze was divided into color-coded quadrants dependent on the complexity, with either 4, 7, or 8 sections to each maze. Each trial was tracked and recorded in order for the research team to measure changes in path length, the time in seconds to reach the exit, and the number of errors defined as the number of entries through a doorway or alley that did not lead to the exit platform.

Performance on the water maze experiment was evaluated following two procedures. The first procedure used normal rats in an apparatus that only included four incorrect choices between open doors and alleys. The rats were placed in the center of the maze and allowed 3 minutes to identify the exit platform; if they did not reach the platform in 3 minutes they were guided down the correct path until they reached the exit. After the subjects were able to complete the maze in 40 seconds with less than 3 errors they were deemed ready to be administered cognition-enhancing nootropics. 30 minutes after the treatment the animals were exposed to the same maze, followed by another 30 minute interval and exposure to a more complicated maze that included 7 incorrect choices instead of 4. The second procedure used rats with a performance deficit induced by NBQX, scopolamine, and alprazolam. These subjects were administered a vehicle, IDRA 21, or aniracetam and were placed in the center of a complex maze that included 8 incorrect choices. This test was repeated 4 consecutive times with 20 minute rest periods in between [3].

The next behavioral test that took place was the passive avoidance experiment. The testing apparatus consisted of two chambers separated by a door that could be raised and an electric shock could be delivered through the floor. Additionally, one side was lighted while the other was completely dark. On the first day of the experiment between 12 and 2 PM, the test subjects weighing between 200 and 250 grams were placed in the lighted side of the apparatus and given access to the dark compartment after 10 seconds. The animals freely explored the two sections over the course of e minutes. 24 hours later the subjects underwent the acquisition trial of the study. After the nootropic or the vehicle was administered, the rats were placed in the light side of the apparatus and the door to the dark compartment was raised after 10 seconds. Once the rat entered the dark compartment the door was closed and a foot shock was delivered, followed by immediate removal and return to their home cage. The retention trial took place 24 hours after the acquisition trial in order for the research team to record the latency to enter the dark compartment over a period of 3 minutes [3].

Following the behavioral studies, electrophysiological studies took place. Neurons from the cerebral cortex were collected from 1 day old Sprague-Dawley rats and plated on glass coverslips in order for electrical recordings to be performed. Ionic currents of the neurons were studied by the whole-cell configuration of the patch clamp technique, followed by recording and storage onto a magnetic tape for the purpose of further data analysis. Furthermore, to evaluate the ionic currents generated by non-NMDA receptors, glutamate was used in the presence of dizocilpine to block the NMDA receptor channels. The researchers measured the steady state of the currents generated by glutamate in either the presence or absence of nootropic drugs in order to assess the ability of the compounds to alter spontaneous desensitization of AMPA receptors.

In addition to neurons of the cerebral cortex. Hippocampal slices were collected from 12-16 day old rats using a vibratome slicer stored in Ringer’s solution for further examination. The hippocampal slices were completely submerged in a 1 ml volume recording studio under continuous perfusion with Ringer’s solution at a rate of 6 ml/minute. Whole-cell current elicited by application of glutamate in the presence of dizocilpine was recorded via voltage clamp in CA1 pyramidal neurons. The researchers also found that the agonist concentration needed to elicit a half-maximal current intensity was approximately 250 uM, while the minimal concentration required to generate a maximum response was approximately 1 mM [3].

 

Discussion

1) The results of the study conducted by Thompson et al initially found that there were individual differences in the control response rates in both the acquisition and performance components of the behavioral testing. When alprazolam was administered in doses of 0.32 mg/kg for females and 0.1 mg.kg for male, the response rates were overall decreased in both components, however, the reduction was more noticeable in the acquisition period. Pretreatment with IDRA 21 was found to counteract the error-increasing effects of alprazolam in a dose-dependent manner in both the acquisition and performance components of the behavioral testing. The lowest dose of IDRA 21 that was shown to affect the rate-decreasing effects of alprazolam was either 0.3 mg/kg or 1 mg/kg depending on whether the subject was male or female [2].

While pretreatment with IDRA 21 reduced the error-increasing effects of alprazolam, administration of the nootropic alone did not result in any significant changes in the measure rate in either component of the behavioral test. This was similar to aniracetam, the parent compound of IDRA 21, that did not elicit any changes in rate or accuracy when administered by itself. Also similar to IDRA 21, aniracetam was found to counteract the rate-decreasing effects of alprazolam in a dose-dependent manner. However, it is important to mention that aniracetam was found to be approximately 10 times less potent than IDRA 21. The attenuation of rate-decreasing with a 30 mg/kg dose of aniracetam was equivalent to that seen with IDRA 21 in 3 mg/kg doses [2].

Figure 1: The effects of IDRA 21 in combination with alprazolam on accuracy and error in both the acquisition and performance components of the behavioral test that was conducted.

Figure 2: The effects of aniracetam in combination with alprazolam on accuracy and error in both the acquisition and performance components of the behavioral test that was conducted.

2) When assessing the effects of IDRA 21 on Sprague-Dawley rats the research team of Zivkovic et all exposed naive rats to a water maze including only 4 incorrect choices, once a day for 2 consecutive days. After their first exposure to the maze the rats were randomly divided into three groups and were administered either IDRA 21, aniracetam, or a vehicle via oral gavage 30 minutes prior to their next exposure to the maze. After the second exposure and a 30 minute rest period the rats were exposed to a more complex maze. The results of the study found that a peroral dose of 65 umol/kg IDRA 21 and a peroral dose of 300 umol/kg of aniracetam did not change the rats performance in the first maze but significantly improved their performance in the second, more complex maze, represented through a decreased number of errors and amount of time to complete the task. The effects of both IDRA 21 and aniracetam peak between 60 and 120 minutes. IDRA 21 was also found to be far more effective than the equimolar dose of the parent compound, aniracetam [3].

Figure 3: Changes in the water maze performance in response to oral administration with IDRA or aniracetam. A) Represents changes in seconds; B) represents changes in the number of errors.

When the test subjects were injected with a pharmacological agent in order to induce a performance deficit, the rats treated with a vehicle were found to not reach the platform in 3 minutes when exposed to a complex maze. The researchers took note of approximately 4500 arbitrary path length units as well as a large number of incorrect choices. However, the researchers noted that when the test subjects were exposed to the maze for three successive trials with 20 minutes between each, the rats learned how to reach the exit platform, made a smaller amount of incorrect choices, and shortened the time and path length to reach the exit platform. By the fourth trial the rats were able to reach the platform without errors in 10 to 15 seconds [3].

In order to disrupt the ability of the test subjects to complete the water maze task the pharmacological agents injected into the rats to induce a performance deficit included NBQX, scopolamine, or alprazolam. The highest doses of these drugs resulted in an increase in arbitrary step units, and an impaired ability to reach the exit platform. Each of these compounds were found to be equally effective in preventing the rats from identifying the position of the exit platform. That being said, both IDRA 21 and aniracetam did not significantly improve water maze performance when administered by themselves, however, they were shown to significantly reduce the performance deficit elicited by injection of NBQX, scopolamine, or alprazolam. A complete reversal of the deficit induced by alprazolam and NBQX was seen with 22 and 43 umol/kg doses of IRDA 21, respectively [3].

Figure 4: Changes in path length during the water maze performance test in response to administration of NBQX, scopolamine, alprazolam, aniracetam, or IDRA 21.

In addition to the water maze test the rats underwent a passive avoidance test. The test subjects were intraperitoneally injected with 0.36 umol/kg of alprazolam 15 minutes before the beginning of their acquisition trial. Once they were placed in the apparatus they entered the dark compartment without delay, indicating a disruption of passive avoidance retention; this behavior was combatted with an oral pretreatment of 43 umol/kg of IDRA 21.

Figure 5: Changes in latency during the passive avoidance test in response administration of a control (cross hatch), IDRA 21 (solid white), alprazolam (solid black), alprazolam + IDRA 21 (horizontal lines), chlorothiazide (diagonal lines upwards), chlorothiazide + alprazolam (grid pattern), diazoxide (diagonal lines downwards), alprazolam + diazoxide (vertical lines)

When assessing the results of the electrophysiological experiments, the cortical neurons’ voltage clamped to record currents in whole-cell mode did not respond to application of IDRA 21 alone. However, in concentrations of 100 uM, IDRA 21 potentiated glutamate non-NMDA currents elicited by glutamate in the presence of dizocilpine. In the hippocampal slices collected, application of 10 uM of IDRA 21 was found to potentiate the non-NMDA current recorded in the voltage clamp CA1 pyramidal neurons and elicited by glutamate. Additionally, the currents elicited by GABA or acetylcholine in the presence of dizocilpine, were unaffected by IDRA 21 [3].

 

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] Buccafusco, Jerry J., Thomas Weiser, Karin Winter, Klaus Klinder and Alvin V. Terry. “The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys.” Neuropharmacology 46 (2004): 10-22

[2] Thompson DM, Guidotti A, DiBella M, Costa E. 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7667-71. doi: 10.1073/pnas.92.17.7667. PMID: 7644474; PMCID: PMC41206.

[3] Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A. 7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid (AMPA) receptor desensitization. J Pharmacol Exp Ther. 1995 Jan;272(1):300-9. PMID: 7815345.

 

 

IDRA-21 is a nootropic compound derived from the chemical structure of benzothiadiazine. Due to its mechanism of action, IDRA-21 is categorized as a member of the ampakine family as the compound primarily works as a positive allosteric modulator of ionotropic glutamate AMPA receptors. AMPA receptors tend to immediately regulate glutamate levels following activation and are widely known for their ability to promote synaptic transmission and plasticity. That being said, IDRA-21 has shown potential in improving cognition and learning while reducing cognitive degeneration typically associated with aging.

As a member of the ampakine family, IDRA-21 is closely related to the compound Aniracetam. Aniracetam is a nootropic that has shown promise in supporting memory formation and retention, mood, and focus. Various animal-based studies have examined how IDRA-21 is capable of reversing cognitive deficits in comparison to Aniracetam. These studies begin by inducing cognitive decline through administration of alprazolam or scopolamine. Subjects, typically rodents, are then treated with either Aniracetam or IDRA-21. Results found that IDRA-21 is not only 10-30 times more potent than Aniracetam, but also stays active for approximately 48 hours.

Effects of IDRA-21 on Memory and Performance

Additional benefits of IDRA-21 are associated with the work of the AMPA receptors that regulate glutamate levels. Cognition and learning tends to be improved through the increase of glutamate levels, leading to the promotion of long term potentiation and synaptic connections throughout the brain. A notable study tested how laboratory rats performed in a water maze following administration of IDRA-21. Results found that the rats receiving IDRA-21 performed far better by exiting the maze faster than those receiving a placebo drug (https://www.linkedin.com/pulse/idra-21-powder-dosage-half-life-benefits-side-effects-wise-powder/).

Another important study conducted by Buccafusco et. Al examined how administering IDRA-21 to both young and old rhesus monkeys affected performance levels. Results of the study were measured by observing the monkeys’ performance of a delayed matching-to-sample (DMTS) test. Doses of IDRA-21 varying from 0.15-10 mg/kg were administered to the test subjects who were then tested at different points of time over a 48 hour testing period. In young monkeys, the most improvement seen in the experimental group was a 34% increase in performance compared to the placebo group. Additional fixed doses given were separated by 3 days in order to see if the compound had a cumulative effect on the monkeys. Researchers observed that over the course of 3 weeks, performance levels gradually increased in the monkeys receiving intermittent doses of the compound.

Aged monkeys, 20-years-old and up, were then given doses of IDRA-21 within the same range as the young monkeys and expected to perform the DMTS test. Results found that over the same dosage range the aged monkeys experienced an increase in overall performance levels, however, the improvement was not as drastic as in the young monkeys. The young monkeys performed at 34% better than those given a vehicle while the aged monkeys performed approximately 18% better than the vehicle. Additionally, the researchers observed that the older monkeys were far more sensitive to variations in the dosage while also exhibiting shorter task latency.

Despite the differences between the old and young experimental groups of monkeys, the data emphasizes the overall improvement seen in both groups without any notable side effects following administration. The improvement in performance in the older monkeys is especially important as it indicates that AMPA receptor modulators such as IDRA-21 can effectively and efficiently assist in combating cognitive decline (https://pubmed.ncbi.nlm.nih.gov/14654093/).

A similar study was conducted specifically in young monkeys that were tasked with completing the same DMTS test as well as a visual recognition test with 4 added delays of 10s, 30s, 60s, and 90s. However, this experiment compared IDRA-21 to a similar cognitive enhancement agent, huperzine A. Huperzine A is known to increase levels of acetylcholine (ACh) in the brain since it acts as an inhibitor of acetylcholinesterase (AChE).

After gathering data on the monkeys’ performance on the two tests, the researchers found huperzine A did not improve performance levels on either task. However, what was interesting about this compound was that it had a negative correlation with the baseline performance levels, so if the monkeys performed poorly at baseline, the drug decreased performance, but if they performed well at baseline there was no additional improvement. On the other hand, the monkeys that were administered IDRA-21 experienced a drastic improvement in performance during the visual recognition task, specifically with the 90s delay. The results of this study solidify the claim that IDRA-21 can work as an effective treatment for cognitive and memory deficiencies (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073152/).

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