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Calcium antagonists fail to protect mammalian spinal neurons after physical injury
Abstract:
Most investigations of calcium antagonists as treatments for experimental spinal cord injury (SCI) have not demonstrated significant reduction of tissue damage or improvement in neurologic outcome. Many of these studies were prompted by reports that these agents increase blood flow to ischemic tissues. However, in vitro studies of renal and neuronal tissues subjected to an anoxic stress have shown that the calcium antagonists can confer direct protection on stressed parenchymal cells. We have used a tissue culture model of nerve cell injury to investigate whether calcium antagonists increase the probability of survival of spinal cord neurons after a defined physical trauma. Preliminary toxicity studies determined the maximum nontoxic dosages of verapamil (80 microM), nifedipine (10 microM), and chlorpromazine (10 microM) for neurons in our cultures. Preselected neurons (100-200 per study) were subjected to amputation of one primary dendrite at a distance of 100 microns from the perikaryon. Erythrosine B tests of viability conducted 24 h after lesioning failed to demonstrate that neurons injured in the presence of any one of these agents had an increased probability of survival compared to operated control neurons. Viability evaluations conducted 2 h after injury with phase contrast microscopy showed no evidence of slowed deterioration. Correction for other lesion physical parameters (lesion diameter and the extent of proximal segment retraction) also failed to reveal any increased protection by these agents. We conclude that calcium antagonists alone will not be useful for treatment of the primary injury of SCI.
Insights
Calcium antagonists do not improve survival for injured spinal cord neurons in vitro. These drugs, including verapamil and nifedipine, failed to protect neurons from physical trauma, indicating they are not useful for treating primary spinal cord injury (SCI).
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Calcium antagonists are investigated for spinal cord injury (SCI) treatment, partly due to their potential to increase blood flow to ischemic tissues.
- In vitro studies suggest calcium antagonists may offer direct cellular protection against anoxic stress in renal and neuronal tissues.
Purpose of the Study:
- To investigate if calcium antagonists enhance the survival of spinal cord neurons following physical trauma using a tissue culture model.
- To determine the efficacy of specific calcium antagonists—verapamil, nifedipine, and chlorpromazine—in protecting neurons from injury.
Main Methods:
- Established maximum nontoxic dosages for verapamil (80 microM), nifedipine (10 microM), and chlorpromazine (10 microM) in cultured neurons.
- Subjected 100-200 neurons per study to physical trauma via amputation of a primary dendrite.
- Assessed neuronal viability 24 hours post-lesioning using Erythrosine B staining and 2 hours post-injury using phase contrast microscopy.
Main Results:
- Neurons injured in the presence of verapamil, nifedipine, or chlorpromazine showed no increased probability of survival compared to controls.
- No evidence of slowed deterioration was observed within 2 hours post-injury.
- Adjustments for lesion physical parameters did not reveal any protective effect from the tested calcium antagonists.
Conclusions:
- Calcium antagonists alone are not effective in treating the primary injury associated with spinal cord injury (SCI).
- The findings suggest that therapeutic strategies for SCI require different approaches beyond the use of these specific calcium antagonists.