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Molecular Dissection of Cyclosporin A's Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury.

Kawakami M - Brain Sci (2013)

Bottom Line: Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation.Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death.It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Aquatic Animal Health Division, National Research Institute of Aquaculture, Fisheries Research Agency, Tamaki, Mie 519-0423, Japan. minkawa@gmail.com.

ABSTRACT
After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction. Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the mechanism underlying CsA's effect on transcriptional regulation.

No MeSH data available.


Related in: MedlinePlus

A model of signaling pathways includes hypothetic transcriptional factor (red ellipse) downstream from CypD (green hexagon). Mitochondria have a special protein pore that is formed in the membranes under certain pathological conditions, such as traumatic brain injury and stroke. This pore is the mitochondrial membrane permeability transition pore, or MPT pore. CypD is a modulator of this pore. VDAC (voltage-dependent anion channel) (blue cylinder) and ANT (adenosine nucleotide translocase) (yellow cylinder) are main components that constitute the MPT pore. An unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD. This factor then translocates from mitochondria to the nucleus and affects transcriptional regulation.
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brainsci-03-01325-f001: A model of signaling pathways includes hypothetic transcriptional factor (red ellipse) downstream from CypD (green hexagon). Mitochondria have a special protein pore that is formed in the membranes under certain pathological conditions, such as traumatic brain injury and stroke. This pore is the mitochondrial membrane permeability transition pore, or MPT pore. CypD is a modulator of this pore. VDAC (voltage-dependent anion channel) (blue cylinder) and ANT (adenosine nucleotide translocase) (yellow cylinder) are main components that constitute the MPT pore. An unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD. This factor then translocates from mitochondria to the nucleus and affects transcriptional regulation.

Mentions: One possible mechanism that could solve this inconsistency is that an unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD, and then this factor translocates from the mitochondria to the nucleus and affects transcriptional regulation. A knockout study found that CypD deficiency worsened hypoxic-ischemic brain injury in neonates [90]. Our results for cDNA subtraction revealed that CsA administration decreased the expression level of complement protein C1q beta, and a previous report showed that neonatal mice with C1q deletion were protected against hypoxic-ischemic brain injury [148,149]. So, it is consistent that this factor suppresses the transcription of detrimental molecules including complement protein C1q beta in the nucleus after the translocation from mitochondria, assuming that CsA assists in this process via its interaction with CypD (Figure 1). In the next section, I will introduce an example of a factor that translocates from mitochondria to the nucleus.


Molecular Dissection of Cyclosporin A's Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury.

Kawakami M - Brain Sci (2013)

A model of signaling pathways includes hypothetic transcriptional factor (red ellipse) downstream from CypD (green hexagon). Mitochondria have a special protein pore that is formed in the membranes under certain pathological conditions, such as traumatic brain injury and stroke. This pore is the mitochondrial membrane permeability transition pore, or MPT pore. CypD is a modulator of this pore. VDAC (voltage-dependent anion channel) (blue cylinder) and ANT (adenosine nucleotide translocase) (yellow cylinder) are main components that constitute the MPT pore. An unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD. This factor then translocates from mitochondria to the nucleus and affects transcriptional regulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061870&req=5

brainsci-03-01325-f001: A model of signaling pathways includes hypothetic transcriptional factor (red ellipse) downstream from CypD (green hexagon). Mitochondria have a special protein pore that is formed in the membranes under certain pathological conditions, such as traumatic brain injury and stroke. This pore is the mitochondrial membrane permeability transition pore, or MPT pore. CypD is a modulator of this pore. VDAC (voltage-dependent anion channel) (blue cylinder) and ANT (adenosine nucleotide translocase) (yellow cylinder) are main components that constitute the MPT pore. An unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD. This factor then translocates from mitochondria to the nucleus and affects transcriptional regulation.
Mentions: One possible mechanism that could solve this inconsistency is that an unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD, and then this factor translocates from the mitochondria to the nucleus and affects transcriptional regulation. A knockout study found that CypD deficiency worsened hypoxic-ischemic brain injury in neonates [90]. Our results for cDNA subtraction revealed that CsA administration decreased the expression level of complement protein C1q beta, and a previous report showed that neonatal mice with C1q deletion were protected against hypoxic-ischemic brain injury [148,149]. So, it is consistent that this factor suppresses the transcription of detrimental molecules including complement protein C1q beta in the nucleus after the translocation from mitochondria, assuming that CsA assists in this process via its interaction with CypD (Figure 1). In the next section, I will introduce an example of a factor that translocates from mitochondria to the nucleus.

Bottom Line: Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation.Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death.It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Aquatic Animal Health Division, National Research Institute of Aquaculture, Fisheries Research Agency, Tamaki, Mie 519-0423, Japan. minkawa@gmail.com.

ABSTRACT
After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction. Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the mechanism underlying CsA's effect on transcriptional regulation.

No MeSH data available.


Related in: MedlinePlus