d-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice
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d-Aspartate (d-Asp) is a free d-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-d-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether d-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with d-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. d-Asp also restored the levels of extracellular d-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike d-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that d-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.
Keywordsd-Aspartate Spared nerve injury Mechanical allodynia Pain-related affective and cognitive behaviour NMDA receptor Mice
This work was financially supported by the Ministero Istruzione, Università e Ricerca, Project n° PRIN 2012WBSSY4_001.
Compliance with ethical standards
Conflict of interest
All the authors who took part in this study declare that they have nothing to disclose regarding competing interests or funding with respect to this manuscript.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed (Animal Ethics Committee of the Second University of Naples in compliance with the IASP and European Community (E.C. L358/1 18/12/86). All procedures were in accordance with the Animal Ethics Committee of the Second University of Naples. This article does not contain any studies with human participants performed by any of the authors.
- Boccella S, Vacca V, Errico F, Marinelli S, Squillace M, Guida F, Di Maio A, Vitucci D, Palazzo E, de Novellis V, Maione S, Pavone F, Usiello A (2015) d-Aspartate modulates nociceptive-specific neuron activity and pain threshold in inflammatory and neuropathic pain condition in mice. Biomed Res Int 2015:905906CrossRefPubMedPubMedCentralGoogle Scholar
- D’Aniello A, Di Fiore MM, Fisher GH, Milone A, Seleni A, D’Aniello S, Perna AF, Ingrosso D (2000a) Occurrence of d-aspartic acid and N-methyl-d-aspartic acid in rat neuroendocrine tissues and their role in the modulation of luteinizing hormone and growth hormone release. FASEB J 14:699–714PubMedGoogle Scholar
- de Bartolomeis A, Latte G, Tomasetti C, Iasevoli F (2014) Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches. Mol Neurobiol 49:484–511CrossRefPubMedGoogle Scholar
- Errico F, Nisticò R, Palma G, Federici M, Affuso A, Brilli E, Topo E, Centonze D, Bernardi G, Bozzi Y, D’Aniello A, Di Lauro R, Mercuri NB, Usiello A (2008a) Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility. Mol Cell Neurosci 37:236–246CrossRefPubMedGoogle Scholar
- Errico F, Nisticò R, Napolitano F, Oliva AB, Romano R, Barbieri F, Florio T, Russo C, Mercuri NB, Usiello A (2011b) Persistent increase of d-aspartate in d-aspartate oxidase mutant mice induces a precocious hippocampal age-dependent synaptic plasticity and spatial memory decay. Neurobiol Aging 32:2061–2074CrossRefPubMedGoogle Scholar
- Errico F, Nisticò R, Di Giorgio A, Squillace M, Vitucci D, Galbusera A, Piccinin S, Mango D, Fazio L, Middei S, Trizio S, Mercuri NB, Teule MA, Centonze D, Gozzi A, Blasi G, Bertolino A, Usiello A (2014) Free d-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals. Transl Psychiatry 4:e417CrossRefPubMedPubMedCentralGoogle Scholar
- Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
- Giordano C, Cristino L, Luongo L, Siniscalco D, Petrosino S, Piscitelli F, Marabese I, Gatta L, Rossi F, Imperatore R, Palazzo E, de Novellis V, Di Marzo V, Maione S (2012) TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception. Cereb Cortex 22:2495–2518CrossRefPubMedGoogle Scholar
- Guida F, Luongo L, Marmo F, Romano R, Iannotta M, Napolitano F, Belardo C, Marabese I, D’Aniello A, De Gregorio D, Rossi F, Piscitelli F, Lattanzi R, de Bartolomeis A, Usiello A, Di Marzo V, de Novellis V, Maione S (2015) Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice. Mol Brain 8:47CrossRefPubMedPubMedCentralGoogle Scholar
- Krashia P, Ledonne A, Nobili A, Cordella A, Errico F, Usiello A, D’Amelio M, Mercuri NB, Guatteo E, Carunchio I (2015) Persistent elevation of d-aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons. Neuropharmacology 103:69–78CrossRefPubMedGoogle Scholar
- Orsetti M, Colella L, Dellarole A, Canonico PL, Ghi P (2007) Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats. Int J Neuropsychopharmacol 10:345–357CrossRefPubMedGoogle Scholar
- Shibata K, Sugaya N, Ono W, Abe K, Takahashi S, Kera Y (2011) Determination of d-aspartate N-methyltransferase activity in the starfish by direct analysis of N-methyl-d-aspartate with high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 879:3229–3234CrossRefPubMedGoogle Scholar