Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease
In the central nervous system (CNS), calcium homeostasis is a critical determinant of neuronal survival. Calpain, a calcium-dependent neutral protease, is widely expressed in the brain, including substantia nigra (SN) dopaminergic (DA) neurons. Though calpain is implicated in human Parkinson’s disea...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/13849 |
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| author | Vandana Zaman Kelsey P. Drasites Ali Myatich Ramsha Shams Donald C. Shields Denise Matzelle Azizul Haque Narendra L. Banik |
| author_facet | Vandana Zaman Kelsey P. Drasites Ali Myatich Ramsha Shams Donald C. Shields Denise Matzelle Azizul Haque Narendra L. Banik |
| author_sort | Vandana Zaman |
| collection | DOAJ |
| description | In the central nervous system (CNS), calcium homeostasis is a critical determinant of neuronal survival. Calpain, a calcium-dependent neutral protease, is widely expressed in the brain, including substantia nigra (SN) dopaminergic (DA) neurons. Though calpain is implicated in human Parkinson’s disease (PD) and corresponding animal models, the roles of specific ubiquitous calpain isoforms in PD, calpain-1 and calpain-2, remain poorly understood. In this study, we found that both isoforms are activated in a nigrostriatal pathway with increased phosphorylated synuclein following the administration of rotenone in Lewis rats, but calpain isoforms played different roles in neuronal survival. Although increased expression of calpain-1 and calpain-2 were detected in the SN of rotenone-administered rats, calpain-1 expression was not altered significantly after treatment with calpain inhibitor (calpeptin); this correlated with neuronal survival. By contrast, increased calpain-2 expression in the SN of rotenone rats correlated with neuronal death, and calpeptin treatment significantly attenuated calpain-2 and neuronal death. Calpain inhibition by calpeptin prevented glial (astroglia/microglia) activation in rotenone-treated rats in vivo, promoted M2-type microglia, and protected neurons. These data suggest that enhanced expression of calpain-1 and calpain-2 in PD models differentially affects glial activation and neuronal survival; thus, the attenuation of calpain-2 may be important in reducing SN neuronal loss in PD. |
| first_indexed | 2024-03-09T18:17:57Z |
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| id | doaj.art-b3698c9774c549a2a0591e18c0e4639e |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:17:57Z |
| publishDate | 2022-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b3698c9774c549a2a0591e18c0e4639e2023-11-24T08:34:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221384910.3390/ijms232213849Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s DiseaseVandana Zaman0Kelsey P. Drasites1Ali Myatich2Ramsha Shams3Donald C. Shields4Denise Matzelle5Azizul Haque6Narendra L. Banik7Ralph H. Johnson Veterans Administration Medical Center, 109 Bee St., Charleston, SC 29401, USAThe Citadel, 171 Moultrie St., Charleston, SC 29409, USAThe Citadel, 171 Moultrie St., Charleston, SC 29409, USAThe Citadel, 171 Moultrie St., Charleston, SC 29409, USADepartment of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas St., Charleston, SC 29425, USARalph H. Johnson Veterans Administration Medical Center, 109 Bee St., Charleston, SC 29401, USARalph H. Johnson Veterans Administration Medical Center, 109 Bee St., Charleston, SC 29401, USARalph H. Johnson Veterans Administration Medical Center, 109 Bee St., Charleston, SC 29401, USAIn the central nervous system (CNS), calcium homeostasis is a critical determinant of neuronal survival. Calpain, a calcium-dependent neutral protease, is widely expressed in the brain, including substantia nigra (SN) dopaminergic (DA) neurons. Though calpain is implicated in human Parkinson’s disease (PD) and corresponding animal models, the roles of specific ubiquitous calpain isoforms in PD, calpain-1 and calpain-2, remain poorly understood. In this study, we found that both isoforms are activated in a nigrostriatal pathway with increased phosphorylated synuclein following the administration of rotenone in Lewis rats, but calpain isoforms played different roles in neuronal survival. Although increased expression of calpain-1 and calpain-2 were detected in the SN of rotenone-administered rats, calpain-1 expression was not altered significantly after treatment with calpain inhibitor (calpeptin); this correlated with neuronal survival. By contrast, increased calpain-2 expression in the SN of rotenone rats correlated with neuronal death, and calpeptin treatment significantly attenuated calpain-2 and neuronal death. Calpain inhibition by calpeptin prevented glial (astroglia/microglia) activation in rotenone-treated rats in vivo, promoted M2-type microglia, and protected neurons. These data suggest that enhanced expression of calpain-1 and calpain-2 in PD models differentially affects glial activation and neuronal survival; thus, the attenuation of calpain-2 may be important in reducing SN neuronal loss in PD.https://www.mdpi.com/1422-0067/23/22/13849calpaindopaminergic neuronalpha-synucleinmicrogliaParkinson’s diseaserotenone |
| spellingShingle | Vandana Zaman Kelsey P. Drasites Ali Myatich Ramsha Shams Donald C. Shields Denise Matzelle Azizul Haque Narendra L. Banik Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease International Journal of Molecular Sciences calpain dopaminergic neuron alpha-synuclein microglia Parkinson’s disease rotenone |
| title | Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease |
| title_full | Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease |
| title_fullStr | Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease |
| title_full_unstemmed | Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease |
| title_short | Inhibition of Calpain Attenuates Degeneration of Substantia Nigra Neurons in the Rotenone Rat Model of Parkinson’s Disease |
| title_sort | inhibition of calpain attenuates degeneration of substantia nigra neurons in the rotenone rat model of parkinson s disease |
| topic | calpain dopaminergic neuron alpha-synuclein microglia Parkinson’s disease rotenone |
| url | https://www.mdpi.com/1422-0067/23/22/13849 |
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