The Mitochondrion in Neurodegeneration and Neuroprotection

Neuroprotection is a novel concept that may result in salvage, recovery or regeneration of brain, its cells, and functions. In contrast neurodegeneration refers to a common pathway for many chronic CNS diseases such as Alzheimer’s disease, Parkinson’s disease, ALS, Huntington’s disease and, at least in part, mental illness.

Neurodegeneration is thought to occur by one of the following mechanisms:

-apoptosis

-oxidative stress

-glutamate excitotoxicity

-stress sensitization

-neurotrophic factors’ dysfunction.

Apoptosis will be described in this essay. Other neurodegenerative mechanisms will be discussed in more detail in future entries.

Mitochondrial breakdown is the hallmark of neurodegenerative diseases. Psychiatric conditions are considered, at least in part, neurodegenerative. Mitochondrial damage was described in both schizophrenia and bipolar disorder.

The mitochondrion is the powerhouse of the neuron. It produces energy from oxygen and glucose. Some neurons may have as many as 1000 mitochondria, depending on their energy need.

The mitochondrion has its own DNA which comes from the mother only. In other words when it comes to the mitochondrion, there is no mixing of parental DNA. Because of this reason, the mitochondrion is prone to more damage as a result of oxidative stress than the rest of the cell.

PRO-APOPTOTIC AND PRO-SURVIVAL FORCES ON THE MITOCHONDRIAL OUTER MEMBRANE

On the outer mitochondrial membrane there are two kinds of proteins. One group facilitates mitochondrial damage (such as BAX). The other group facilitates mitochondrial repair (such as Bcl-2).

Bax protein damages the mitochondrion by perforating the outer membrane, forming pores. Bcl-2 protein protects the mitochondrial outer membrane by patching these pores.

Bcl-2 gene family codes for both groups of pro-survival and pro-apoptotic proteins.

Bcl-2 is a family of genes that produce both pro-survival and pro-apoptotic proteins. BAX is a death-promoting (pro-apoptotic) protein that inflicts damage (open pores) to the outer mitochondrial membrane.

Bcl-X and Bcl-2 genes produces proteins that are able to patch the pores of the outer mitochondrial membrane, thus evading apoptosis.

Bax protein is like a woodpecker, it literally drills holes into the mitochondrial outer membrane, leading to the formation of pores. Enzymes from the mitochondrial matrix and citochrome C pour out through the pores, activate caspases (executioners proteins) and eventually destroy the mitochondrion (autophagy) or the cell (apoptosis).

AUTOPHAGY, APOPTOSIS AND NECROSIS

This is how it all works: when the mitochondrion is under oxidative stress, either Bcl-2 or BAX gene is activated. If the damage cannot be repaired, it leads to the formation of the mitochondrial pore, inducing autophagy, catabolism of the mitochondrion only. This is a positive process since the cell is salvaged and only the mitochondrion is lost.

As the oxidative damage of the mitochondrion increases, molecules such as cytochrome C may be released from mitochondria leading to the apoptosis of the whole cell.

At the extreme, oxidative stress may causes rupture of the mitochondrial membrane, inducing necrosis (acute cell death).

Autophagy and apoptosis require energy (ATP), necrosis is a passive process and it does not require ATP.

Caspase Activation

When the mitochondrial damage is too extensive and cannot be repaired by Bcl-2 protein, caspase are activated, leading to apoptosis. Caspases are a family of proteases (executioner proteins) that orchestrate apoptosis. Fourteen mammalian caspases have been identified, three of which (caspase-3, -6, and -7) are thought to coordinate the execution phase of the neuron.

Biological Markers of Neurodegenerative Diseases

UNWANTED APOPTOSIS: in neurodegenerative diseases such as Alzheimer’s disease, caspase 3 is constantly elevated because of the ongoing active cell death, also the BAX/Bcl-2 ratio is elevated because cells are prone to apoptosis.

FAILURE OF APOPTOSIS: in cancer caspase 3 and the BAX/Bcl-2 ratio are low because cancer cells are resistant to apoptosis. Indeed intra-tumoral BAX protein injections proved beneficial as cancer therapy.

Schizophrenia is a neurodegenerative disease only in part because the BAX to Bcl-2 ratio is elevated (excessive BAX gene activation), but unlike Alzheimer’s disease or Parkinson’s, it lacks the caspase 3 activation (execution phase). There is no active cell death in schizophrenia, yet there is evidence of neuronal atrophy and synaptic loss in some areas of the brain.

These changes could reflect either a pathophysiological failure to mount an effective response to an apoptotic insult, or an apoptotic compensatory response to an earlier insult.

Unable to solve this dilemma, scientists proposed the localized apoptosis theory. It claims that the neurons themselves do not die, but the dendrites and synapses undergo autophagy (inadequately termed local apoptosis).

Final stage of a white blood cell apoptosis

In conclusion: Most neurodegenerative diseases commence with the imbalance between pro-survival and pro-apoptotic proteins on the mitochondrial outer membrane.

Failure of apoptosis is considered one of the causes of cancer and autoimmune diseases.

Unwanted apoptosis occurs with ischemia, Parkinson’s disease or Alzheimer's disease. For this reason the interest in caspases as potential therapeutic targets for neurodegenerative diseases, excluding schizophrenia, has constantly increased since the mid-1990s when they were first discovered.

Some Psychotropic Drugs Protect the Mitochondrion by Increasing Bcl-2

During the past few years research has focused on developing neuroprotective agents for the therapy of various degenerative diseases, including Alzheimer’s, ALS, Parkinson’s disease and mental illness. Neuroprotection is an effect that may result in salvage, recovery or regeneration of brain, its cells, structure and function. This hypothesis is based on new evidence that psychiatric disorders are associated with neuronal atrophy and cell loss in some areas of the brain.

Lithium and Valproate as a Neuroprotective Agents

In a recent clinical study, researchers found that dysfunctional autophagy was the final common pathway in the genesis of Amyotrophic Lateral Sclerosis(ALS).

Lithium administration slowed the progression of ALS in human patients. It is believed that lithium desensitizes brain mitochondria to calcium, and diminishes cytochrome c release, preventing initiation of apoptosis.Another recent study showed that chronic lithium treatment markedly increased the levels of the major neuroprotective protein bcl-2 in frontal cortex, hippocampus, and striatum.

It is now believed that lithium not only upregulates Bcl-2, but downregulates pro-apoptotic BAX, and inhibits caspase 3.

Other studies demonstrated that lithium has neuroprotective effects in animal and cellular models of Alzheimer’s disease, Huntington’s disease, Parkinsons’s disease, retinal degeneration, spinal cord injury and HIV infection.

Valporic acid was also found to be neuroprotective by increasing the level of Bcl-2 protein as well.

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Valproate and lithium were found to increase Bcl-2 in the frontal cortex, the striatum and hippocampus.

Antidepressants as Neuroprotective Agents

The SSRI fluoxetine was found to upregulate Bcl-2 in the hippocampus, but not in the frontal cortex or the striatum. SSRIs also upregulate BDNF.

Pramipexole as Neuroprotective Agent

Pramipexole is the presynaptic dopamine agonist which is FDA approved for the treatment of Parkinson’s disease and restless leg syndrome. Pramipexole upregulates Bcl-2 protein in different areas of the brain. Pramipexole also upregulates BDNF.

Olanzapine and Clozapine as Neuroprotective Agents

In animal models, administration of Olanzapine or Clozapine upregulated Bcl-2 in the frontal cortex and the hippocampus (Hammonds 2009; also Bai O, Zhang 2004). Also in human neuroblastoma, clozapine or olanzapine, but not haloperidol, prevented the decrease in Bcl-2 (Kim NR, 2008)

Neuroprotective Non-Psychotropic Drugs

Many non-psychotropic drugs were also found to have neuroprotective action. They will be mentioned here briefly, but discussed in more detail in future essays.

Pregnenolone and DHEA,

Estrogen

Erythropoietin

Rasagiline

S-Adenosylmethionine

Sirtuins

Piracetam

L-Theanine

Retinoids

ADONIS SFERA, MD