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Nefiracetam is a nootropic antidementia drug of the racetam family.

Nefiracetam's cytoprotective actions are mediated by enhancement of GABAergic, cholinergic, and monoaminergic neuronal systems. It has been shown to effectively treat apathy and improve motivation in post-stroke patients. It has been shown to exhibit antiamnesia effects for the Alzheimer's type and cerebrovascular type of dementia. In addition, it has also been shown to have antiamnesia effects against a wide variety of memory impairing substances, including: ethanol, chlorodiazepoxide (Librium), scopolamine, bicuculline, picrotoxin, and cycloheximide.

Pharmacokinetics
Nefiracetam is usually administered orally. Nefiracetam is an uncharged molecule and is lipid soluble, allowing it to easily pass through the blood brain barrier. In a study done in healthy male volunteers, nefiracetam was given in single doses ranging from 10-200mg and in multiple doses with 200mg of the drug given to subjects 3 times a day for seven days. Blood serum concentrations of nefiracetam reach a peak after 2 hours. The half life of the drug is 3-5 hours.

Action on ACh Receptors
The ACh system is affected by memory disorders such as Alzheimer’s disease, and thus nefiracetam has been shown to act via ACh receptors to improve memory. When nefiracetam is administered in submicromolar amounts, short-term depression in ACh dependent currents occurs. The depression is caused by nefiracetam acting on Gs protein-regulated, cAMP-dependent PKA which leads to subsequent ACh receptor phosphorylation. Long term enhancement of ACh currents can be achieved when nefiracetam is applied at micromolar concentrations. This enhancement is caused by nefiracetam acting on calcium dependent PKC which causes subsequent phosphorylation of PKC receptors. However, the specific type of PKC pathway is still unknown.

Action on GABA Receptors
Nefiracetam has been shown to bind GABAA receptors and modulate the receptor activity. High concentrations of nefiracetam and low concentrations of GABA evoked strong chloride currents, while high concentrations of GABA in the presence of nefiracetam suppressed these currents. This suggests that nefiracetam acts via a slowly mediated intracellular pathway, of which the exact mechanism is not yet known, and that there exists an optimal level of intracellular nefiracetam that causes increased chloride currents. In the presence of nefiracetam, glutamate decarboxylase activity has been shown to increase, which leads to increased GABA levels and also to enhance GABA uptake.

Action on Voltage-Gated Calcium Channels
Research has demonstrated that the memory enhancing properties of nefiracetam functionality are also mediated by voltage-gated calcium channels. The action of nefiracetam on different kinds of calcium channels varies. Nefiracetam causes long lasting currents in voltage-gated calcium channels, however blockage of L-type and N-type calcium channels attenuates the memory enhancing effects of nefiracetam. This suggests that the effects of nefiracetam may be mediated by L and N-type channels, which in turn may be regulated by inhibitory G-proteins and cAMP dependent processes.

Action on NMDA Receptors
Since NMDA receptors are implicated in learning and memory, nefiracetam has been thought to act via these receptors in order to enact its memory enhancing properties. Nefiracetam binds to the glycine site of NMDA receptors and acts like an agonist to induce NMDA receptor currents. As long-term potentiation (LTP) is induced through NMDA receptors via activation of CaMKII and PKC pathways, it is thought that nefiracetam also activates these pathways to produce its memory enhancing qualities.

Action on Monoamines
Nefiracetam increases levels of enzymes responsible for synthesis of dopamine, serotonin, and norepinephrine. Metabolites for these monoamines (MHPG, DOPAC, and 5-HIAA) were found to be higher in the hippocampus, frontal cortex, hypothalamus, and striatum after chronic nefiracetam administration in mouse models. However, these increases in monoamine levels are not dependent on the dosage of nefiracetam and are region specific.

Alzheimer's Disease
Nefiracetam has been mainly used in the treatment of Alzheimer’s disease. Amyloid-beta peptides are implicated in the formation of senile plaques in Alzheimer’s patients. In rats infused with AB-peptide, nefiracetam was found to increase the rats’ performance on a Y-maze task and water maze task by increasing working memory and spatial reference abilities. Since nefiracetam works to activate voltage gated calcium channels, it is thought that more ACh and dopamine are released through this pathway and therefore ameliorates the effects of AB-peptide plaques in these rats.

Reduction in glutamatergic signaling is also implicated in the learning and memory deficits associated with Alzheimer’s disease. In experiments done in rat hippocampal CA1 slices, bath applications of nefiracetam were shown to induce LTP in NMDA mediated currents, thus showing nefiracetam as a novel treatment for Alzheimer’s. Nefiracetam has been found to act on the glycine binding site of NMDAR’s after no potentiation was seen when 7-CIKN, an NMDAR antagonist that acts at the glycine site, was administered to the bath. LTP induction by nefiracetam causes CaMKII autophosphorylation and phosphorylation of synapsin I (Ser-603) and AMPA-type glutamate receptor subunit 1 (GluA1) (Ser-831). The fact that nefiracetam increases NMDAR activity and CaMKII phosphorylation, which are downregulated in Alzheimer’s patients, suggests that nefiracetam has cognitive enhancing abilities.

Amnesia
Research has shown that nefiracetam improves amnesia induced by scopolamine, bicuculline, picrotoxin, ethanol, chlordiazepoxide, and cycloheximide in rat models. Nefiracetam improved learning impairments by increasing acetylcholine release, GABA turnover, and glutamate decarboxylase activity while also activating N and L type calcium channels. Activation of multiple systems results in increased protein synthesis, similar to protein synthesis in LTP, and therefore causes amelioration of induced amnesia and correction of learning impairments.

Side Effects
Studies of long term consumption of nefiracetam in humans and primates have shown it to have no toxicity. However, animals which metabolize nefiracetam differently from humans and primates are at risk for renal and testicular  toxicity. Dogs especially are particularly sensitive, which has been shown to be caused by a specific metabolite, M-18. Nefiracetam caused infolding of epithelial cells and and necrotic lesions in the papillary ducts of the dogs, suggesting that papillary epithelial cells are the main target for nefiracetam in the onset of renal papillary necrosis. In another experiment done in male dogs, nefiracetam was observed to lower testosterone levels by impairing the mechanism that converts progesterone to testosterone in Leydig cells. There was also decreased sperm motility and increased instances of malformed sperm observed from semen samples. Examination of the testis showed severe seminiferous atrophy in these dogs, showing that nefiracetam may cause testicular toxicity. Higher doses than those in dogs were needed to cause testicular toxicity in rats, although no toxicity was seen in monkeys. Additionally, there has been no evidence of toxicity during clinical trials.