Coluracetam: What is Coluracetam?
Coluracetam: What is it?
Coluracetam, also known as MKC-231, is a tetrahydro-furoquinolone analogue with an International Union of Pure and Applied Chemistry (IUPAC) name of N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide (US National Library of Medicine, 2012). Coluracetam is further classified as a nootropic agent or cognitive enhancer, specifically a choline uptake stimulant. It was originally developed as treatment for Alzheimer’s disease, but it failed to achieve endpoints in Phase II of clinical trial wherein administration involved a larger patient sample (Benson, 2005). Only about a third of patients experienced benefits, and no delay in disease progression was noted. Coluracetam was since marketed purely as a cognitive enhancer.
Mechanism of Action
The exact mechanism of action of coluracetam is unknown given the dearth in primary studies, but it
is thought to be related to the neurotransmitter acetylcholine. Choline is actively transported into the presynaptic neuron and combines with acetate to form acetylcholine (Barnes, 2013). This neurotransmitter plays a role in cognition based on lesion studies showing that administering cholinergic antagonists led to learning, attention, and memory deficits as do conditions that result in the basal forebrain complex destruction (Barnes, 2013; Hasselmo, 2006). This area of the brain, specifically the medial septum, is innervated by cholinergic subnuclei as in the hippocampus.
Conventional treatment approaches have been with prolonging the breakdown of acetylcholine by antagonizing the enzyme acetylcholinesterase (Benson, 2005). In laboratory studies, regeneration of cholinergic subnuclei and grafts with acetylcholine-producing neurons has been shown to reverse cognitive deficits (Davis et al., 2002). While the administration of acetylcholinesterase antagonists may be beneficial in some diseases, it is ineffective in Alzheimer’s disease because the latter involves the progressive loss of cholinergic neurons. The reduced production of acetylcholine, therefore, renders the administration of acetylcholinesterase antagonist of little benefit.
The action of coluracetam is an alternative strategy to addressing the inadequate production of acetylcholine. It enhances the uptake of choline by neurons and the presynaptic release of acetylcholine (Shirayama et al., 2007). When the physiologic demand for acetylcholine is unusually high, it activates the high-affinity choline uptake (HACU) system that regulates the transportation of choline into the neuron terminal for the synthesis of acetylcholine (Williams College, 2002). Coluracetam or MKC-231 improves the HACU system by enhancing the signaling of high-affinity choline transporters (Ruggiero et al., 2012; Takashina et al., 2008). Increased active transport of choline contributes to greater acetylcholine synthesis.
Uses of Coluracetam
A study by Murai et al. (1994) showed that the chronic administration of coluracetam was associated with the reversal of working memory deficiencies and reductions in acetylcholine in the hippocampus in a mouse model. These effects were significantly greater compared with other nootropics, namely linopiridine and tetrahydroaminoacridine. Effects were also significant for all three doses of once-daily oral coluracetam – 0.3, 1.0, or 3.0 mg per kg – during the 11-day trial.
A comparative study by Bessho et al. (1996) of coluracetam and tacrine, an acetylcholinesterase, in a rat model validated the enhanced effect of the drug on the HACU system as compared with tacrine but only in diseased rats. There was no effect on normal rats. At the same time, coluracetam improved memory and water maze learning in the diseased rats without any major side effects whereas tacrine even in high doses had no effect on learning but resulted in tremor, hypothermia or salivation.
In a rat model of schizophrenia induced by phencyclidine, carbachol, and cocaine, Shirayama et al. (2007) sought to determine if treatment with coluracetam alleviated the cellular and behavioral deficits associated with exposure. The results showed that coluracetam reversed the locomotor dysfunction noted in rats exposed to carbachol and cocaine as well as the cognitive deficits noted following phencyclidine exposure. In addition, the drug also halted the decline in choline acetyltransferase cells in the medial septum that are indispensable in acetylcholine synthesis. The results suggest further investigation to ascertain the possibility of coluracetam as a treatment of schizophrenia.
In a more recent study, Bessho et al. (2008) followed up on their research on water-maze learning in rats with cognitive impairments. The authors administered 1-3 mg/kg of coluracetam and investigated the effects on the HACU system and learning at one hour and 24 hours after administration. Further follow up at 48 and 72 hours after the last doses were also conducted. Cognitive improvement was noted at 24 hours. HACU trends over time showed increase implying a sustained and longer-term reversal in cognitive deficits even after the last dose.
Coluracetam has also been licensed out as an investigatory neurogenesis enhancer for the treatment of depression and anxiety with the Phase 2 human clinical trial already concluded although study results are yet to be published (Safety and effectiveness, 2011). The involvement of the hippocampus in mood disorders, the effect of neurogenesis on this part of the brain, and the role of coluracetam in this process prompted the clinical trial. On a broader perspective, the company holding the patent to the drug aims to develop coluracetam as a prophylactic treatment against or actual treatment of diseases of the central and peripheral nervous system, including degenerative, ischemic, learning, memory, mood, and anxiety disorders as well as trauma and psychosis (Mitsubishi Tanabe Pharma, 2007). The basis of the patent are the effects of coluracetam on neural stem cell culture analysis and brain cell differentiation studies.
Coluracetam Dosage, Usage, Effects, and Side Effects
Despite the status of coluracetam as an investigational drug with no published results of the trial establishing the dose, effects, and side effects in humans, websites are already advocating its use as a supplement for enhancing brain power. Suggested doses for supplement use are based on rat studies and thus were recommended to be between 2.5 – 3 mg/kg orally. In the patent for coluracetam as treatment for depression and anxiety, the dose used ranged from 80 mg orally once to three times daily. Coluracetam is commonly dosed from 50-150 mg with most nootropic users. No side effects have been noted in rat and mouse studies and side effects in humans are yet to be reported.