TABLE.
Studies testing the potential neuroprotective effect of dantrolene in animal or cell models are listed by injury model, animal model, timing of dantrolene administration in relation to the injury, dantrolene dose, findings, and the citation.
| Injury | Model | Timing of Dantrolene Relative to Injury | Dose of Dantrolene | Findings | Citation |
|---|---|---|---|---|---|
| Excitotoxicity (NMDA) | Cortical neuron culture | at the time of injury | 30 μM | iCa2+ reduced by 30% in presence of extracellular Ca2+ and 100% in absence of extracellular Ca2+; toxic effect of glutamate entirely prevented | 7 |
| Excitotoxicity (Glutamate, NMDA, QA, KA, AMPA) | Cortical neuron culture | at the time of injury | 30 μM | Dantrolene blocks LDH and calcium release by NMDA, QA and glutamate, no effect on KA or AMPA | 48 |
| Excitotoxicity (NMDA) | Cerebellar granule neuron culture | 45 min prior | 1-100 μM alone and in combination with nimodipine and ruthenium red (RuR) | dose-dependent neuroprotection at 5 and 15 min, alone and in combination with RuR and nimodipine | 44 |
| Excitotoxicity (NMDA,KA, QA) | Cerebellar granule neuron culture | Simultaneous | 50 μM | Dantrolene inhibited glutamate induced Ca2+-release | 45 |
| Excitotoxicity (NMDA) | Cerebellar granule neuron culture | at the time of injury | 5-30 μM | decrease in iCa2+ in response to NMDA and K+, proving that NMDA/K+ released Ca2+ from intracellular stores | 46 |
| Excitotoxicity (NMDA) | Mixed cortical and retinal cell cultures | at the time of injury | 30 μM | iCa2+ decreased by 56%; cell toxicity reduced by 50% | 49 |
| Excitotoxicity (NMDA) | Hippocampal neuron culture | 10-20 min prior | 10 μM | reduced NMDA-induced increased iCa2+ | 50 |
| Neurotoxicity by 3-HK | Cerebellar granule neuron culture, PC12 cells, and GT1-7 hypothalamic neurosecretory cells | 30 min prior | 120 μM | 3-HK induced cell death of PC12 and GT1-7 cells inhibited; marked increase in protein level Bcl-2 | 58 |
| HIV-1 infection (cytotoxicity by HIV coat protein gp 120) | Cortical synaptosomes | Immediately prior and 10 min during experiment | 10 μM | decreased Gp120-induced iCa2+ rise | 109 |
| Status epilepticus | Kainic acid 8 mg/kg, rat | 30-60 min after | 10 mg/kg i.p. (approx 40 μM) | CA3 protected and CA1 preserved at 4 days | 110 |
| Status epilepticus (140min) | Electrogenic limbic status epilepticus, rat | Simultaneous, 30 or 140 min after onset | 10 mg/kg i.p. (approx 40 μM) | early administration reduced injury in all areas of hippocampus, late administration reduced injury in CA3 region | 82 |
| Epilepsy | Rat | 15, 30, or 60 min prior | 62.5 mg/kg, 125 mg/kg, 250mg/kg, 500 m/kg, all i.p. (approx 250-2000 μM) | dose dependent reduction in limbic seizures | 84 |
| Epilepsy | EL mouse (mutant susceptible to convulsive seizures) | 60 min prior | 20, 40 and 80 mg/kg i.p (approx 80-320 μM) | Seizure suppression; no influence on NO levels at any dose | 111 |
| Epilepsy | Hippocampal slice, rat | n/a | 10-100 μM | Dose-dependent suppression of pilocarpine- and DHPG-induced ictal activity | 17 |
| Epilepsy | Entorhinal cortex and hippocampus slice, rat | 30 min prior and during | 30 μM | complete cell death prevention after 1, 3, or 12-14hrs; no effect on synaptic transmission or epileptic discharges | l6 |
| OGD(0-15min) | intracellular recordings in cortical slice, rat | 15 min prior | 10-30 μM | no effect on membrane depolarization or intracellular calcium increase | 112 |
| OGD (40min) | Hippocampal slice, rat | 120 min prior or simultaneously or 120 min after | 10 μM | No effect | 77 |
| OGD(0-10min) | Hippocampal slice, gerbil | 60 min prior and during | 50 μM | Dantrolene reduced iCA2+ increase from ER | 79 |
| OGD (10-16 hours) | Neuroblastoma cell line | Simultaneous or 16 hours or 48 hours after | 40 and 80 μM | viability doubled at 48 hours; treatment after OGD achieves same effect as during OGD | 80 |
| OGD (40min) | Neonatal cortical slice | 0-40 or 40-120 min after | 20 μM | early but not late energy failure reduced | 54 |
| OGD (45 min) | Retinal cell culture, rat | 30 min prior and during | 100 μM | ganglion cell death prevented; 54% reduction of dead cells in the retinal layer | 47 |
| OGD (48 hrs) | Cortical neuron cell culture with presenlin-1 expression | 60 min prior | 10 μM | 80% of neurons rescued | 71 |
| Forebrain ischemia (20 min) | 4 vessel occlusion, rat | 15 min prior | 20 μM topical | Reduction of free fatty acids from ischemia and reperfusion | 113 |
| Forebrain ischemia (3 min) | Gerbil | 30 or 120 min after | 6μ1 of 1.6 mM intracerebroventricular (approx 10 μM in the brain); 0.4mM solution (approx 2.5 μM in brain) | 3 and 4.5 fold neuronal protection for 0.4 and 1.6mM. No effect at 120 min. | 81 |
| Forebrain ischemia (5 min) | 4 vessel occlusion, rat | 15 min after followed by infusion for 3 days | 33 μg intracerebroventricular (approx 50 μM) followed by 40 μg/day (approx 60 μM) | 50% CA1 cell loss reduction at 4 days; reduced TUNEL staining in the CA1 region. | 114 |
| Forebrain ischemia (10 min) | 4 vessel occlusion, rat | 15 min prior | 33 μg intracerebroventricular (approx 50 μM) | 40% more viable neurons in CA1 at 7 days. | 51 |
| Focal ischemia (90 min) | Middle cerebral artery occlusion, rat | Immediately after | 20 μg intracerebroventricular (approx 30 μM) | 65% infarct volume reduction at 24 hours; reduced ER stress markers and TUNEL staining in the penumbra | 68 |
| Focal ischemia (120 min) | Middle cerebral artery occlusion, rat | 30 min prior | 2 mg/kg (approx 8 μM) | No effect | 78 |
| Global cerebral ischemia (11 min) | Dog | Immediately prior | 4mg/kg intravenous (approx 16 μM) | No effect | 76 |
| Apoptosis (in vitro); global ischemia (in vivo) | GT1-7 hypothalamic neurosecretory cells (in vitro), gerbil (in vivo) | 30min prior (in vitro), Immediately after (in vivo) | 120 and 240 μM (in vitro); 10, 25, and 50 mg/kg intravenous (approx 40-200 μM) | Dose-dependent reduction of iCa2+, DNA-fragmentation and cell death (in vitro). dose-dependent increase of CA1 cells at 7 days (in vivo); 50mg/kg was toxic. | 15 |
| Apoptosis | PC12 cells | 120 min prior | 1 μM | Suppression of peroxide accumulation and protection against oxidative stress | 57 |
| Apoptosis (in vitro) / status epilepticus (in vivo) | Cerebellar granule neuron culture (in vitro) and rat (in vivo) | Simultaneous (in vitro), 60 min prior (in vivo) | 10 μM (in vitro); 10 mg/kg i.p. (approx 40 μM, in vivo) | cell death and apoptosis decreased at 3h and 24h (in vitro). CA1 region and cerebral cortex protected against apoptosis at 24hrs (in vivo) | 60 |
| Apoptosis (in vivo) | Hypoxic-ischemic neonatal rat brain | Immediately after | 1 mM intracerebroventricular | Lip/Cr ratio decreased (1H MR spectroscopy) at 24hrs; no effect on NAA/Cr ratio; infarct area decreased at 14d; no effect on TUNEL stain and survival rate at 14d. | 61 |
| Membrane fluidity | Neuroblastoma cell line | Immediately after | 10 μM | Dantrolene decreased Ca2+ mobilization by 40%, reduced increase in membrane fluidity and stabilized neuronal plasma cell membranes | 66 |
| Spinal cord injury (mechanical compression) | Ex-vivo spinal cord, rat | 15 min prior until 20min after | 10 μM | Electrophysiological recovery improved 1h after injury | 18 |
| Trauma | Hippocampal neuron culture | Simultaneously | 30 μM and 100 μM | Dose-dependent reduction in cell death | 115 |
Abbreviations: NMDA, N-methyl-D-aspartate; QA, quisqualate; KA, Kainate; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; 3-HK, 3-hydroxykynurenine; HIV-1, human immunodeficiency virus type-1; gp120, glycoprotein; mGluR, metabotropic glutamate receptor; 1S,3R-ACPD, (1S,3R)-1-aminocyclopentane-1-3-dicarboxylic acid; OGD, oxygen glucose deprivation; PC, pheochromocytoma cells; RuR, ruthenium red; ip., intraperitoneal; iCa2+, intracellular calcium; LDH, lactate dehydrogenase; NO, nitric oxide; DHPG, dihydroxyphenylglycine; ER, endoplasmic reticulum; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling; TTC, tetrazolium chloride; Lip/Cr, lipid/creatine; NAA/Cr, N-acetyl aspartate/creatine.