Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain.
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.
Neurotune AG, Wagistrasse 27a, CH-8952 Schlieren, Switzerland. Electronic address: ruggero.fariello@neurotune.com.
Ruggero G
RG
Fariello
Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale Pieraccini 6, I-50139 Florence, Italy. Electronic address: carla.ghelardini@unifi.it.
Carla
C
Ghelardini
Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale Pieraccini 6, I-50139 Florence, Italy. Electronic address: lorenzo.mannelli@unifi.it.
Lorenzo
L
Di Cesare Mannelli
Department of Pharmacy, Pharmacology and Toxicology Unit, University of Genoa, Viale Cembrano 4, I-16148 Genoa, Italy. Electronic address: bonanno@pharmatox.unige.it.
Giambattista
G
Bonanno
Department of Pharmacy, Pharmacology and Toxicology Unit, University of Genoa, Viale Cembrano 4, I-16148 Genoa, Italy. Electronic address: pittalug@pharmatox.unige.it.
Anna
A
Pittaluga
Department of Pharmacy, Pharmacology and Toxicology Unit, University of Genoa, Viale Cembrano 4, I-16148 Genoa, Italy. Electronic address: milanese@pharmatox.unige.it.
Marco
M
Milanese
NiKem Research, Via Zambeletti 25, I-20021 Baranzate, Milan, Italy. Electronic address: paola.misiano@unimi.it.
Paola
P
Misiano
Neurotune AG, Wagistrasse 27a, CH-8952 Schlieren, Switzerland. Electronic address: carlo.farina@neurotune.com.
Carlo
C
Farina
D000704:Analysis of Variance; D000818:Animals; D044966:Anti-Retroviral Agents / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D020370:Osteoarthritis, Knee / Q000150:complications; D017239:Paclitaxel / Q000633:toxicity; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation / Q000009:adverse effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014750:Vincristine / Q000633:toxicity; D016474:Weight-Bearing / Q000502:physiology
D044966:Anti-Retroviral Agents; D000972:Antineoplastic Agents, Phytogenic; D007093:Imidazoles; D011758:Pyrroles; D016194:Receptors, N-Methyl-D-Aspartate; C085079:dimiracetam; D014750:Vincristine; D017239:Paclitaxel
Glutamate; Neuropathic pain; Nootropics