Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain

doi:10.1016/j.neuropharm.2014.01.029

Neuropharmacology

Volume 81, June 2014, Pages 85-94

https://doi.org/10.1016/j.neuropharm.2014.01.029 Get rights and content

Highlights

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The nootropic drug dimiracetam shows high efficacy in several neuropathic pain models.
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Chronic dimiracetam treatment strongly increases both efficacy and duration of action.
•
Dimiracetam inhibits glutamate release via novel NMDA receptor subtypes.

Abstract

Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anecdotal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis. Chronic dimiracetam dosing in the MIA and ART- induced models completely reverted hyperalgesia back to the level of healthy controls. Once reached, the maximal effect was maintained despite dose diminution and increased inter-dose interval. The effect of the last dose outlasted dimiracetam half-life longer than 12 times. In synaptosomal preparations, dimiracetam counteracted the NMDA-induced release of glutamate with highest potency in the spinal cord, possibly via NMDA receptor isoforms containing pH-sensitive GluN1 and GluN2A subunits. Dimiracetam appears to be a promising and safe treatment for neuropathic pain conditions for which there are very limited therapeutic options.

Introduction

There is dire need for improved treatment of neuropathic pain (Dworkin and Turk, 2011). There is no evidence that class I NSAIDs have any benefit in this indication. The presently available pharmacopoeia offers a handful of antidepressants and anticonvulsants with proven efficacy in some neuropathic pain conditions (Edelsberg et al., 2011). Outside of these, only topical capsaicin, a substance P vesicle-depleting agent, at high concentration has provided clinical confirmation of usefulness (Derry et al., 2013). When these approaches fail, physicians revert to opioid derivatives, which entail pharmacological, medical and social adversities. Nevertheless, the safety/efficacy ratio of all these compounds is far from satisfactory. The need is so compelling that the FDA has promoted ACTION, a consortium of public and private entities to join forces in addressing some of the glaring gaps still hampering the development of innovative treatments in this field (Dworkin et al., 2011).

One of the early stumbling blocks during drug development regards the predictability of clinical efficacy based on established animal (mostly rodents) models of human neuropathic syndromes. Efficacy on a single animal model offers little probability of a direct extrapolation to clinical conditions, whereas a broad spectrum of action on several models may offer greater reliability.

Racetam derivatives, called nootropics, are a family of 2-pyrrolidinone derivatives originally designed in the sixties as GABA analogs and profiled as cognition enhancers. After failing to provide robust evidence of improving cognition in degenerative dementia (Malykh and Sadaie, 2010), this indication was abandoned. Levetiracetam (Gower et al., 1992) is highly efficacious as an antiepileptic drug and has controversial evidence of potential benefit in headaches (Beran and Spira, 2011, Capuano et al., 2004, Krusz, 2001) and other forms of neuropathic pain (Holbech et al., 2011, Mitsikostas et al., 2010). A report of efficacy of nefiracetam against tactile and thermal hyperalgesia in mice (Rashid and Ueda, 2002) suggested that chemical modifications of the racetam structure might confer powerful antineuropathic pain activity.

Thus, several classes of novel 2-pyrrolidinone derivatives were synthesized with the aim of obtaining compounds effective in animal models of neuropathic pain. This program envisaged a screening funnel starting from demonstration of anti-hyperalgesic efficacy in the chronic constriction injury (CCI) model in rats after intra-cerebro-ventricular administration (Farina et al., 2008). After this gating step, effective compounds proceeded further on the basis of their drugability properties and were tested after systemic administration on several other models of neuropathic pain. In addition, reassessment of dimiracetam (Pinza et al., 1993) in neuropathic pain models showed broad spectrum efficacy and an excellent tolerability profile, retaining at the same time its outstanding efficacy of improving cognition in animal models.

We are here reporting the efficacy profile of dimiracetam in several rodent models of neuropathic pain, together with the unique property of prolonging its efficacy and maintaining a full anti-hyperalgesic response upon chronic administration after reducing the initial dose to one fourth, without any evidence of drug accumulation.

In addition, the biochemical effects of dimiracetam on the NMDA/glycine-induced neurotransmitter release in spinal synaptosomes were assessed.

Section snippets

Animals

All animal handling and experimental protocols were approved by the Institutional Animal Care and Use Committee. The experiments were carried out in accordance with the Animal Protection Law of the Republic of Italy, DL No. 116/1992, based on the European Community Council Directive of Nov. 24 1986 (86/609/EEC). All efforts were made to minimize animal suffering and to reduce the number of animals used. Animals were group-housed in approved facilities under a fixed light dark cycle (7 a.m–7

Dimiracetam pharmacokinetics in rats

As reported in Table 1, dimiracetam half life (T_1/2) was 276 min (4.6 h) after single oral dose of 100 mg/kg with a C_max of 536 μM. On steady state, after two weeks oral dosing at 100 mg/kg b.i.d. the kinetic parameters of dimiracetam demonstrated a T_1/2 of 337 min (5.6 h) with a C_max of 741 μM. The plasma levels after a 14-day dosing of dimiracetam at 100 mg/kg b.i.d. resulted in a C_max higher than after a single administration, at 60 min, but also with a higher clearance, since plasma levels

Discussion

Nefiracetam was the first of several racetam molecules found effective in animal models of neuropathic pain (Rashid and Ueda, 2002) acting through various mechanisms of action, ranging from protein kinase mediated neurotransmission to α₄β₂ nicotinic receptors modulation (Moriguchi et al., 2009, Moriguchi, 2011). Scattered evidence in the literature suggests also efficacy of levetiracetam in models of neuropathic (Ardid et al., 2003, Ozcan et al., 2008) or inflammatory (Micov et al., 2010) pain;

Conflict of interest statement

Ruggero G. Fariello and Carlo Farina are currently consultants to Neurotune AG. All the other authors performed the work in the framework of research contracts with Neurotune AG. This study was performed without any financial or other contractual agreements that may cause conflict of interest.

Acknowledgments

We thank Paola Petrillo, Jan W Vrijbloed and Roberto Maj for assistance and useful discussion.

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Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain

Highlights

Abstract

Introduction

Section snippets

Animals

Dimiracetam pharmacokinetics in rats

Discussion

Conflict of interest statement

Acknowledgments

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Cancer

Neuropharmacology

Neurosci. Lett.

Pain

Bioorg. Med. Chem.

Eur. J. Pharmacol.

Prog. Neurobiol.

Eur. J. Pain

Pain

Brain Res.

Prog. Neurobiol.

Neuroscience

J. Pharmacol. Sci.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pain

Pain

Neurosci. Lett.

Adv. Drug Deliv. Rev.

A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man

Pain

Levetiracetam in chronic daily headache: a double-blind, randomised placebo-controlled study (The Australian KEPPRA Headache Trial [AUS-KHT])

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