Calcium channel blockers and dementia
Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellul...
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| Veröffentlicht in: | British journal of pharmacology 2013-07, Vol.169 (6), p.1203-1210 |
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| description | Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid‐β. Recent studies suggest that soluble forms facilitate influx through calcium‐conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid‐β‐induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof‐of‐concept studies are now available. |
| doi_str_mv | 10.1111/bph.12240 |
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Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid‐β. Recent studies suggest that soluble forms facilitate influx through calcium‐conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid‐β‐induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof‐of‐concept studies are now available.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.12240</identifier><identifier>PMID: 23638877</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer Disease - metabolism ; Alzheimer Disease - physiopathology ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Animals ; Brain - drug effects ; Brain - metabolism ; Calcium ; calcium antagonists ; Calcium Channel Blockers - therapeutic use ; calcium channels ; Calcium Channels - chemistry ; Calcium Channels - metabolism ; Calcium Channels, L-Type - chemistry ; Calcium Channels, L-Type - metabolism ; Calcium Signaling - drug effects ; Dementia - drug therapy ; Dementia - metabolism ; Dementia - physiopathology ; Disease Progression ; Drugs, Investigational - therapeutic use ; Humans ; Molecular weight ; Neurodegeneration ; Neurons - drug effects ; Neurons - metabolism ; Nootropic Agents - therapeutic use ; Reviews ; Synaptic Transmission - drug effects ; vascular dementia</subject><ispartof>British journal of pharmacology, 2013-07, Vol.169 (6), p.1203-1210</ispartof><rights>2013 The British Pharmacological Society</rights><rights>2013 The British Pharmacological Society.</rights><rights>British Journal of Pharmacology © 2013 The British Pharmacological Society</rights><rights>British Journal of Pharmacology © 2013 The British Pharmacological Society 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4760-569760bf28a7e242400c2aa18a490e73306357bdb736a0fb83e9b75060aab56e3</citedby><cites>FETCH-LOGICAL-c4760-569760bf28a7e242400c2aa18a490e73306357bdb736a0fb83e9b75060aab56e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831702/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831702/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23638877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nimmrich, V</creatorcontrib><creatorcontrib>Eckert, A</creatorcontrib><title>Calcium channel blockers and dementia</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid‐β. Recent studies suggest that soluble forms facilitate influx through calcium‐conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid‐β‐induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof‐of‐concept studies are now available.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - physiopathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animals</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Calcium</subject><subject>calcium antagonists</subject><subject>Calcium Channel Blockers - therapeutic use</subject><subject>calcium channels</subject><subject>Calcium Channels - chemistry</subject><subject>Calcium Channels - metabolism</subject><subject>Calcium Channels, L-Type - chemistry</subject><subject>Calcium Channels, L-Type - metabolism</subject><subject>Calcium Signaling - drug effects</subject><subject>Dementia - drug therapy</subject><subject>Dementia - metabolism</subject><subject>Dementia - physiopathology</subject><subject>Disease Progression</subject><subject>Drugs, Investigational - therapeutic use</subject><subject>Humans</subject><subject>Molecular weight</subject><subject>Neurodegeneration</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Nootropic Agents - therapeutic use</subject><subject>Reviews</subject><subject>Synaptic Transmission - drug effects</subject><subject>vascular dementia</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kF1LwzAUhoMobk4v_ANSEEEvup00zcduBB3qBEEv9Dokaeo603Y2q7J_b7RzqGBuzsV5eM-bB6FDDEMc3kgvZkOcJClsoT5OOYspEXgb9QGAxxgL0UN73s8BwpLTXdRLCCNCcN5HJxPlTNGWkZmpqrIu0q42L7bxkaqyKLOlrZaF2kc7uXLeHqznAD1dXz1OpvHd_c3t5OIuNuEqxJSNw9B5IhS3SRoKgUmUwkKlY7CcEGCEcp1pTpiCXAtix5pTYKCUpsySATrvchetLm1mwvFGObloilI1K1mrQv7eVMVMPtdvkgiCOSQh4HQd0NSvrfVLWRbeWOdUZevWS0wZBCHpmAb0-A86r9umCt8LVCIYYSLlgTrrKNPU3jc235TBID_lyyBffskP7NHP9hvy23YARh3wXji7-j9JXj5Mu8gPiT6L2A</recordid><startdate>201307</startdate><enddate>201307</enddate><creator>Nimmrich, V</creator><creator>Eckert, A</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>201307</creationdate><title>Calcium channel blockers and dementia</title><author>Nimmrich, V ; Eckert, A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4760-569760bf28a7e242400c2aa18a490e73306357bdb736a0fb83e9b75060aab56e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - physiopathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Animals</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Calcium</topic><topic>calcium antagonists</topic><topic>Calcium Channel Blockers - therapeutic use</topic><topic>calcium channels</topic><topic>Calcium Channels - chemistry</topic><topic>Calcium Channels - metabolism</topic><topic>Calcium Channels, L-Type - chemistry</topic><topic>Calcium Channels, L-Type - metabolism</topic><topic>Calcium Signaling - drug effects</topic><topic>Dementia - drug therapy</topic><topic>Dementia - metabolism</topic><topic>Dementia - physiopathology</topic><topic>Disease Progression</topic><topic>Drugs, Investigational - therapeutic use</topic><topic>Humans</topic><topic>Molecular weight</topic><topic>Neurodegeneration</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Nootropic Agents - therapeutic use</topic><topic>Reviews</topic><topic>Synaptic Transmission - drug effects</topic><topic>vascular dementia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nimmrich, V</creatorcontrib><creatorcontrib>Eckert, A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nimmrich, V</au><au>Eckert, A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Calcium channel blockers and dementia</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2013-07</date><risdate>2013</risdate><volume>169</volume><issue>6</issue><spage>1203</spage><epage>1210</epage><pages>1203-1210</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid‐β. Recent studies suggest that soluble forms facilitate influx through calcium‐conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid‐β‐induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof‐of‐concept studies are now available.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>23638877</pmid><doi>10.1111/bph.12240</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer Disease - physiopathology Alzheimer's disease Amyloid beta-Peptides - metabolism Animals Brain - drug effects Brain - metabolism Calcium calcium antagonists Calcium Channel Blockers - therapeutic use calcium channels Calcium Channels - chemistry Calcium Channels - metabolism Calcium Channels, L-Type - chemistry Calcium Channels, L-Type - metabolism Calcium Signaling - drug effects Dementia - drug therapy Dementia - metabolism Dementia - physiopathology Disease Progression Drugs, Investigational - therapeutic use Humans Molecular weight Neurodegeneration Neurons - drug effects Neurons - metabolism Nootropic Agents - therapeutic use Reviews Synaptic Transmission - drug effects vascular dementia |
| title | Calcium channel blockers and dementia |
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