Aniracetam is a pyrrolidinone compound of the racetam family, and has an additional anisoyl ring with a methoxy group at the lone para position. (replacing the amine group of piracetam) with an O-methoxy group on the furthest binding point. Its structure is dissimilar to that of oxiracetam (which is quite similar to piracetam) and Pramiracetam (fairly unique structure) yet closely related to that of nefiracetam.
Aniracetam is a piracetam molecule in which the amine is replaced by a methylated phenyl group, this modification was made to enhance fat solubility and underlies differences between piracetam and aniracetam
2.1. Ion Channels
Aniracetam as well as the structurally similar Nefiracetam are able to enhance long-lasting calcium channel currents in neurons at concentrations as low as 1µM.
3.1. Absorption and bioavailability
Aniracetam appears to be greatly taken up from the gut even in a fasted state, but is subject to extensive first pass hepatic metabolism. Due to this, it has an overall bioavailabiliy of around 8.6-11.4%. Bioavailability is presumed higher when taken with fatty acids, but unexplored.
Is fat-soluble and logically enhanced when taken with fatty acids, does not appear to need fatty acids to be absorbed
Plasma levels of aniracetam have been noted to peak at 2.3mcg/L (300mg) and 14.1mcg/L (1200mg) with an elimination half life of 35 minutes following ingestion of aniracetam. It appears to have extensive first pass metabolism in the liver with the main metabolites being N-anisoyl-GABA, 2-pyrrolidinone, and anisic acid. 95.8% of the dose is recovered, mostly in the urine, 28 hours post ingestion.
In a study of healthy male volunteers, Aniracetam showed a Cmax (max concentration) of 8.75+/-7.82 and 8.65+/-8.7ng/mL over two testing periods which correspond to a Tmax (time at max) of 0.4+/-0.1 hour each time; in response to 400mg oral Aniracetam. The plasma elimination half-lives were 47+/-0.16 and 49+/-0.24 hours and plasma AUC 4.53+/-6.62 and 4.76+/-6.65ng/h/mL in this study as well. These relatively low peaks of Aniracetam may be due to extensive metabolism after oral administration.
It appears that superloading Aniracetam (50-100mg/kg bodyweight) does not augment the Cmax or Tmax significantly, and tends to only prolong the AUC to 1.7-2.1 hours.
Appears to be rapidly absorbed in under 30 minutes, and rapidly metabolized; higher doses do not change the time it takes to work, but may prolong the AUC (Area-Under-Curve) of Aniracetam, either by delaying excretion or metabolism
The main human metabolite of Aniracetam is a compound known as N-Anisoyl-GABA (aka. 4,p-Anisaminobutyric acid or ABA), which accounts for 70% of orally ingested Aniracetam by weight after hepatic (liver) biotransformation. Alternate pathways lead to production of P-Anisic Acid (which can be conjugated by wither glucuronic acid or glycine) and 2-pyrrolidinone (which then goes on to the Kreb's Cycle to produce energy via the succinate intermediate).
One study that confirmed protective effects against amnesia in a choice reaction test with aniracetam (10-100mg/kg) subsequently tested all metabolites, with both P-anisic acid and 2-pyrrolidinone failing to exert anti-amnesiac effects while N-anisoyl-GABA at 30mg/kg was similarly effective.
Aniracetam is heavily metabolized into N-anisoyl-GABA and P-Anisic Acid, which should be considered for bioactivity in the body
4.1. Glutaminergic Neurotransmission
AMPA is one of the three subsets of glutamate (excitatory) receptors, of which the other two are kainate and NMDA (N-methyl-D-Aspartate). These AMPA receptors mediate fast excitatory amino acid transmission, and are heterogenously expressed in the brain as heteromers with eight possible subunits (GluR1 through R4, each in a flip or flop variant).
Aniracetam is a modulator of the AMPA receptor that works by binding to a non-active site of AMPA receptors and allosterically modifying the binding site, of which the final result is a reduced rate of desensitization in the presence of positive stimuli (such as glutamate, which is intrinsically produced). This occurs in the concentration range of 1-5mM.
AMPA receptors appear to be positively modulated by aniracetam, similar to other basic racetam compounds
Aniracetam has been noted to be a positve modulator of kainate receptors.
Aniracetam does not directly agonize NDMA receptors, but does not appear to hinder agonism of NMDA receptors either.
May have a positive influence on kainate receptors, does not appear to interact with NMDA receptors much if at all
4.2. Adrenergic Neurotransmission
Activation of AMPA receptors is able to release noradrenaline from neurons, and 100µM (but not 10µM) of aniracetam is able to potentiate AMPA's effects on noradrenaline release in these hippocampal cells.
Kyurenic acid is able to attenuate the ability of NDMA to release noradrenaline from cells, and this inhibition is attenuated in the presence of aniracetam (EC50 in the range of 10-100nM and near full inhibition at 1µM) without inherently affecting basal outflow or NMDA induced release of noradrenaline at this dose; blocking the AMPA receptor failed to block this effect, and while kyurenic acid also suppresses AMPA receptor activation aniracetam (1-100µM) does not antagonize this effect (cyclothiazide, however, was effective).
4.3. GABAergic Neurotransmission
Aniracetam appears to enhance the effects of corticol GABAergic inhibition independent of NMDA.
4.4. Cholinergic Neurotransmission
Aniracetam appears to be able to potentiate signalling via nicotinic α4β2 receptors at 0.1nM via interactions with GS proteins, independent of protein kinases.
4.5. Dopaminergic Neurotransmission
Aniracetam has been shown at 50mg/kg oral ingestion (rats) to decrease the turnover rates for dopamine in the striatum and reducing dopamine levels in the hypothalamus and striatum; serotonin levels decreased in the hypothalamus but increased in the cortex and striatum, where it reduced turnover (hypothalamus) and increase turnover (cortex, striatum, brain stem).
Aniracetam seems to be able to alleviate damage done to memory and learning impairment caused by various agents and traumas such as cholinergic antagonists, cerebral ischaemia and electroconvulsive shock. Aniracetam can also protect against scopolamine-induced damage, and does so (at 1.5g) to a greater extent than Piracetam (at 2.4g).
4.7. Anxiety and Depression
Aniracetam has been shown to reduce measures of anxiety in rats, and has anecdotally reported to do the same in humans. It is suspected to do so via a mix of serotonergic, dopaminergic, and cholinergic interactions. Improvements as measured by social interactions were seen in doses ranging from 10mg/kg body weight to 100mg/kg bodyweight.
It has demonstrated efficacy in reducing depression in aged rats at 100mg/kg bodyweight, but was ineffective at exerting anti-depressive effects in younger mice. These effects were mimicked with Aniracetam metabolites, and were abolished with haloperidol and mecamylamine, and thus the mechanism was theorized to be enhancing dopaminergic signalling via the nicotinic acetylcholinergic receptors.
There may also be interactions with depression and downstream effects of Aniracetam's main mechanism of action, AMPA receptor modulation.
4.8. Memory and Learning
Aniracetam has been found to specifically decrease the rate of receptor desensitization in lab animal hippocampus (specifically quisqualate receptors), suggesting a potential benefit to memory formation. It does not seem affect choline uptake into hippocampal cells in any way, and actually encourages acetylcholine release.
Aniracetam also increases the release of dopamine and serotonin via cholinergic mechanisms in the prefrontal cortex, with implications in improving judgement. This may also in part explain it's involvement as an anti-depressant. Via either the same or alternate mechanisms (positive AMPA modulation) Aniracetam has also been shown to reduce impulsiveness in the rat.
Through the general mechanism of AMPA modulation (and thus applicable to Piracetam and Oxiracetam), Ampakines can upregulate Brain-derived Neurotrophic factor (BDNF) for, although the effects can attentuate rapidly via reduced AMPA receptor levels. One study perfomed on rat hippocampus slices in vitro suggested that that AMPA receptor attenutaion can be avoided by stimulating the cultures for 24 hrs, followed by a 24 hr washout period. The 24 hrs on/ 24 hrs off stimulation protocol was able to maintain increased levels of BDNF expression over a 5 day period.
Further studies on rat hippocampus slices cultured in vitro suggest that AMPA receptor attenuation can similarly be circumvented with a daily dosing protocol of 3 hrs. More research is needed to determine whehter such attenuation can be avoided in vivo with a similar intermittent dosing protocol.
Since BDNF is implicated in increasing adult neural plasticity, such studies would be of great interest in the neurology field.
5Interactions with Disease States
It is also being studied in other cognitive deficits such as Alzheimer's disease or other cognitive ailments as either a mechanism to biologically reverse neurological changes or to alleviate symptoms of said disorders.
5.2. Fetal Alcohol Syndrome
Aniracetam has also been implicated in rats to alleviate some cognitive deficits in the hippocampus onset by Fetal Alcohol Syndrome (FAS) in a dosage of 50mg/kg bodyweight.