Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury
Abstract
:1. Introduction
2. Neuroprotective Drugs
2.1. Antioxidants
2.1.1. NXY-059 (Cerovive)
Categories | Drugs | Current status/Result of clinical trial |
---|---|---|
Antioxidants | NXY-059 (Cerovive) | Trial in a larger number of cases indicated no significant activity. The program was terminated. |
Tirilazad | The drug increased the combined endpoint of “death or disability” by about one-fifth. | |
Nicaraven | The drug did not demonstrate enough therapeutic efficacy in the treatment of acute ischemic stroke. | |
Ebselen | A phase III trial exploring the efficacy in patients with cortical infarct is under way. | |
SUN-N8075 | A phase I trial is under way in the United States. | |
Calcium Antagonists | Nimodipine | A clinical trial once suggested a beneficial effect, but none of the subsequent trials confirmed this result. |
Monosialoganglioside GM1 | There is not enough evidence to conclude that gangliosides are beneficial in acute stroke. | |
Nootropil (Piracetam) | There is not enough evidence to assess the effect of piracetam in acute ischemic stroke. | |
E-2051 | A phase I clinical trial is under way in Europe. | |
N-methyl-D-aspartate (NMDA) Receptor Antagonists | Selfotel | The drug was not effective and might have a neurotoxic effect in brain ischemia. |
Gavestinel | There is no evidence of benefit. Further development has been discontinued. | |
Magnesium | No beneficial effects on the functional outcome of stroke in patients were accrued except in cases of lacunar syndromes. | |
GABA Agonists | Clomethiazole | The drug did not improve outcome in patients with major ischemic stroke. |
Sodium Channel Blockers | lubeluzole | The drug failed to show the efficacy in the treatment of acute stroke. |
Opioid Antagonists | nalmefene | A phase III study was completed, but the results were not published. |
Membrane Stabilizers | Citicoline | The drug was not efficacious in the treatment of moderate-to-severe acute ischemic stroke. |
DP-b99 | The Phase III trial is under way. | |
Poly ADP-ribose Polymerase (PARP) Inhibitors | ONO-2231 | A Phase I clinical trial is under way in the UK. |
AX200 (Granulocyte Colony-Stimulating Factor (G-CSF)) | The drug failed to show the efficacy in the treatment of acute stroke. | |
Immunosuppressants | FK506 (Tacrolimus) | A human stroke trial was stopped in phase II. |
Cyclosporin A | A Phase II clinical trial, Neuroprotection Impact of Cyclosporin A in Cerebral Infarction (CsAStroke), is under way. | |
PTP inhibitors | Pramipexole(Mirapex) | No information about clinical trial for an inhibitor of PTP. |
S-15176 | No information about clinical trial for an inhibitor of PTP. | |
Others | Albumin | A Phase III randomized multicenter clinical trial of high-dose human albumin therapy for neuroprotection in acute ischemic stroke. |
ONO-2506 (Proglia) | A Phase III crinical trial in acute stroke patients was completed and failed to show the efficacy of the drug in the treatment of acute stroke. | |
SUN-N4057 (Piclozotan) | Phase II clinical trials are under way in the USA and Europe. | |
TS-011 | Phase I clinical trials of TS-011 are under way. |
2.1.2. Tirilazad
2.1.3. Nicaraven
2.1.4. Ebselen
2.1.5. SUN-N8075
2.2. Calcium Antagonists
2.2.1. Nimodipine
2.2.2. Monosialoganglioside GM1
2.2.3. Nootropil (Piracetam)
2.2.4. E-2051
2.3. N-Methyl-D-Aspartate (NMDA) Receptor Antagonists
2.3.1. Selfotel
2.3.2. Gavestinel
2.3.3. Magnesium
2.4.GABA Agonists: Clomethiazole
2.5.Sodium Channel Blockers: Lubeluzole
2.6.Opioid Antagonists: Nalmefene
2.7. Membrane Stabilizers
2.7.1. Citicoline
2.7.2. DP-b99
2.8. Poly ADP-Ribose Polymerase (PARP) Inhibitors
2.8.1. ONO-2231
2.8.2. AX200 (Granulocyte Colony-Stimulating Factor (G-CSF))
2.9. Albumin
2.10. ONO-2506 (Proglia)
2.11. SUN-N4057 (Piclozotan)
2.12. TS-011
3. Immunosuppressants
3.1. FK506 (Tacrolimus)
3.2. Cyclosporin A
- Acute: TBI, SCI, stroke, and cerebral vasospasm following subarachnoid hemorrhage (SAH).
- Chronic: neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD).
- Selective neuronal brain protection from radiotherapy for brain cancer.
4. Agents That Modulates/Inhibits PTP
4.1. CsA as a Neuroprotective Agent
- (1)
- CypD deficiency resulted in a significant reduction of hypoxic-ischemic brain injury in adult mice but worsened injury in neonates.
- (2)
- CypD-deficient cells also responded to various apoptotic stimuli in a manner similar to that of the WT, suggesting that CypD is not a central component of the apoptotic death pathway.
4.2. Other PTP Inhibitors
4.2.1. Pramipexole (Mirapex)
4.2.2. S-15176
5. CsA’s Effect on Transcriptional Regulation
5.1. Analysis of the Effects of CsA Administration on Gene Expression
- easy and cost-effective
- applicable when levels of starting material are minimal
- does not require prior knowledge of the transcriptomes
- can detect not only mRNA but also a variety of other RNA species (e.g., miRNA, siRNA)
- can obtain candidate cDNA clones during the analysis.
- Gene-chip is fast, simple, and shows more coverage
- Gene-chip does not need cloning or sequence steps.
5.2. Materials and Methods
5.2.1. CsA Administration
5.2.2. Tissue Preparation and RNA Preparation
5.2.3. cDNA Subtraction and Isolation of the Candidate Clones
5.3. Results of cDNA Subtraction Experiment
5.3.1. Significantly Upregulated Genes
5.3.2. Significantly Downregulated Genes (Group 1)
5.3.3. Significantly Downregulated Genes (Group 2)
5.4. Discussion
- CsA appears to affect the expression of many genes related to neuronal cell survival and regeneration.
- Many of the significantly upregulated genes identified in the present study are reported to be neurotrophic or have roles in the regeneration of damaged neurons.
- CsA reduces the expression of some genes that were reported to be detrimental to neuronal cells.
- CsA reduces the expression of certain genes that appear to be important for oxidative metabolism.
6. An Example of Mitochondria-Nuclear Communication; Prohibitin 1 (PHB1)
7. Conclusion
Abbreviations
AD: | Alzheimer’s disease |
ALS: | amyotrophic lateral sclerosis |
ANT: | adenosine nucleotide translocase |
BDNF: | brain-derived neurotrophic factor |
CaM: | calmodulin |
CCP: | classical complement pathway |
CsA: | Cyclosporin A |
CypD: | cyclophilin-D |
G-CSF: | granulocyte-colony stimulating factor |
HD: | Huntington’s disease |
HETE: | hydroxyeicosatetraenoic acid |
HIF-1: | hypoxia Inducible factor-1 |
IL-1: | interleukin-1 |
IL-2: | interleukin-2 |
MCAO: | middle cerebral artery occlusion |
MDH: | malate dehydrogenase |
MPT: | mitochondrial membrane permeability transition |
MS: | multiple sclerosis |
NF-AT: | nuclear factor of activated T-cells |
NMDA: | N-methyl-D-aspartate |
PARP: | poly ADP-ribose polymerase |
PD: | Parkinson’s disease |
PGK-1: | phosphoglycerate kinase 1 |
SAH: | subarachnoid hemorrhage |
SCI: | spinal cord injury |
STAT3: | signal transducers and activator of transcription 3 |
TBI: | traumatic brain injury |
VDAC: | voltage dependent anion channel |
VDC: | voltage-dependent calcium channel |
Acknowledgments
Conflicts of Interest
References
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Kawakami, M. Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury. Brain Sci. 2013, 3, 1325-1356. https://doi.org/10.3390/brainsci3031325
Kawakami M. Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury. Brain Sciences. 2013; 3(3):1325-1356. https://doi.org/10.3390/brainsci3031325
Chicago/Turabian StyleKawakami, Minoru. 2013. "Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury" Brain Sciences 3, no. 3: 1325-1356. https://doi.org/10.3390/brainsci3031325