Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease
| Autor: | Michael J. O'Neill, M. Broadstock, S. N. Mitchell, Susan Duty, Paul J. Austin, M. J. Betts |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Microdialysis Glutamic Acid Nigrostriatal pathway Substantia nigra Motor Activity Biology Receptors Metabotropic Glutamate Neuroprotection Rats Sprague-Dawley Phosphoserine Internal medicine Excitatory Amino Acid Agonists medicine Animals Pharmacology Aspartic Acid Pars compacta Aminobutyrates Glutamate receptor Parkinson Disease Immunohistochemistry Research Papers Symptomatic relief Rats Substantia Nigra Disease Models Animal Neuroprotective Agents medicine.anatomical_structure Endocrinology Metabotropic receptor Metabotropic glutamate receptor sense organs |
| Zdroj: | British Journal of Pharmacology. 160:1741-1753 |
| ISSN: | 1476-5381 0007-1188 |
| DOI: | 10.1111/j.1476-5381.2010.00820.x |
| Popis: | Background and purpose: Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson's disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD. Experimental approach: Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [3H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats. Key results: l-SOP and l-AP4 inhibited [3H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects. Conclusions and implications: These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects. |
| Databáze: | OpenAIRE |
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