N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide, (CAS Number) 77191-36-7, (PubChem) CID 71157, (ChemSpider) 64299, (UNI) 1JK12GX30N, (ChEMBL) CHEMBL260829, C14H18N2O2
Nefiracetam is a substance in the Racetam family that has received attention as a treatment for seizures, depression, and dementia as of recent and despite studies showing toxicity in rats and dogs does not appear to have any long-term toxicity in humans. More research needs to be conducted to further elucidate the effects of Nefiracetam on depression, especially in stroke patients.
Mechanism of Action For Nefriacetam
Nefiracetam appears to have two main mechanisms of action; the mechanism of action most often cited in research is potentiating NMDA receptors through protein kinase C, as opposed to through agonism of NMDA receptors [7,10]. NMDA has been shown to have direct correlation to memory function and neuroplasticity. The other mechanism of action cited is Nefiracetams ability to potentiate activity of nicotinic acetylcholine receptors, leading to greater release of GABA and glutamate neurotransmitters .
The benefits of Nefiracetam appear to fall into three main categories; Nefiracetam can be used in the treatment of seizures (both convulsive and non-convulsive), can be used as an antidepressant, and is neuroprotective and potentially cognitive enhancing.
Nefiracetam has shown potential in treating seizures (both convulsive and non-convulsive); in one study, it was shown that Nefiracetam doses ranging from 25 to 100mg/kg (in rats) greatly reduced the effects of amygdala based seizures. However, Nefiracetam had no significant effect on stopping seizures from occurring . In another study, it was shown that Nefiracetam at the dose of 30mg/kg (in rats) taken prior to a stroke greatly reduces the number and duration of seizures that may occur post-stroke .
There have been two major studies conducted on the use of Nefiracetam in the treatment of depression; the first study looked at using Nefiracetam to treat post-stroke depression. This study administered 900mg to adult stroke patients and found that it was not significantly effective in treating depression, but was effective in treating severely clinically depressed patients . The second study looked at Olfactory Bulbectomized rats and found Nefiracetam to be effective in ameliorating depressive behaviors at a dose of 1mg/kg .
Nefiracetam has also been noted to have some neuroprotective and Nootropic effects in studies conducted; in one study on kainic acid induced seizures in rats, Nefiracetam was found to attenuate the damage to the rat hippocampus when administered at doses of up to 100mg/kg . Another study found Nefiracetam aids in protecting neurons from experiencing cell death when administered Veratridine, which is a neurotoxin . Nefiracetam was also found to improve spatial learning ability in rats who have suffered cerebral embolism .
Based on the studies cited, the recommended dosage for Nefiracetam lies between 8.721mg/kg and 29.072mg/kg in humans for treating the negative cognitive effects of seizures as well as treating severely depressed individuals [1,3,4,9,12].
Nefiracetam was found to be extremely testicular toxic in both rats (at 1500mg/kg) and dogs (at doses as low as 180mg/kg); it was found to significantly decrease the levels of testicular testosterone leading to atrophy and malformation of sperm. These results have not been tested in humans, and further experimentation needs to be conducted before any form of generalization can occur [6,13]. Beyond the testicular toxicity in rats and dogs, no toxicity has been found to occur in humans in doses up to 900mg .
Kitano Y, Komiyama C, Makino M, Takasuna K, Satoh H, Aoki T, Kinoshita M, Takazawa A, Yamauchi T, Sakurada S. Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats. New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. firstname.lastname@example.org 
Moriguchi S, Shioda N, Han F, Narahashi T, Fukunaga K. CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. email@example.com 
Robinson RG, Jorge RE, Clarence-Smith K. Double-blind randomized treatment of poststroke depression using nefiracetam. Department of Psychiatry, The University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA. firstname.lastname@example.org 
Kitano Y, Komiyama C, Makino M, Kasai Y, Takasuna K, Kinoshita M, Yamazaki O, Takazawa A, Yamauchi T, Sakurada S. Effects of Nefiracetam, a novel pyrrolidone-type nootropic agent, on the amygdala kindled seizures in rats. New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo. email@example.com 
Han F, Nakano T, Yamamoto Y, Shioda N, Lu YM, Fukunaga K. Improvement of depressive behaviors by nefiracetam is associated with activation of CaM kinases in olfactory bulbectomized mice. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan. 
Shimada M, Shikanai Y, Shimomura K, Harada S, Watanabe G, Taya K, Kato M, Furuhama K. Investigation of testicular toxicity of nefiracetam, a neurotransmission enhancer, in rats. Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan. 
Moriguchi S, Han F, Shioda N, Yamamoto Y, Nakajima T, Nakagawasai O, Tadano T, Yeh JZ, Narahashi T, Fukunaga K. Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan. firstname.lastname@example.org 
Moriguchi S, Zhao X, Marszalec W, Yeh JZ, Fukunaga K, Narahashi T. Nefiracetam and galantamine modulation of excitatory and inhibitory synaptic transmission via stimulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA. 
Lu XC, Dave JR, Chen Z, Cao Y, Liao Z, Tortella FC. Nefiracetam attenuates post-ischemic nonconvulsive seizures in rats and protects neuronal cell death induced by veratridine and glutamate. Branch of Brain Trauma and Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. Electronic address: email@example.com. 
Moriguchi S, Shioda N, Maejima H, Zhao X, Marszalec W, Yeh JZ, Fukunaga K, Narahashi T. Nefiracetam potentiates N-methyl-D-aspartate (NMDA) receptor function via protein kinase C activation and reduces magnesium block of NMDA receptor. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611-3008, USA. 
Moriguchi S. Pharmacological study on Alzheimer’s drugs targeting calcium/calmodulin dependent protein kinase II. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan. firstname.lastname@example.org 
Le DT, Shin C, Jackson-Friedman C, Lyden PD. Quantitative effects of nefiracetam on spatial learning of rats after cerebral embolism. Department of Neurosciences, UCSD School of Medicine, and Neurology, Veterans Administration Medical Center, San Diego, CA, USA. 
Shimomura K, Shimada M, Hagiwara M, Harada S, Kato M, Furuhama K. Testicular toxicity induced in dogs by nefiracetam, a neutrotransmission enhancer. Drug Safety Research Laboratory, Daiichi Pharmaceutical Co, Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. email@example.com