The Mitochondrion in Neurodegeneration and NeuroprotectionNeuroprotection 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 diseasessuch as Alzheimer’s disease, Parkinson’s disease, ALS, Huntington’s disease and, at least in part, mentalillness.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 inmore detail in future entries.Mitochondrial breakdown is the hallmark of neurodegenerative diseases. Psychiatric conditions areconsidered, at least in part, neurodegenerative. Mitochondrial damage was described in bothschizophrenia and bipolar disorder.The mitochondrion is the powerhouse of the neuron. It produces energy from oxygen and glucose. Someneurons 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 tothe mitochondrion, there is no mixing of parental DNA. Because of this reason, the mitochondrion isprone 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 MEMBRANEOn the outer mitochondrial membrane there are two kinds of proteins. One group facilitatesmitochondrial 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 proteinprotects 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 adeath-promoting (pro-apoptotic) protein that inflicts damage (open pores) to the outermitochondrial membrane.Bcl-X and Bcl-2 genes produces proteins that are able to patch the pores of the outer mitochondrialmembrane, 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 pourout through the pores, activate caspases (executioners proteins) and eventually destroy themitochondrion (autophagy) or the cell (apoptosis).AUTOPHAGY, APOPTOSIS AND NECROSISThis is how it all works: when the mitochondrion is under oxidative stress, either Bcl-2 or BAX gene isactivated. If the damage cannot be repaired, it leads to the formation of the mitochondrial pore, inducingautophagy, catabolism of the mitochondrion only. This is a positive process since the cell is salvagedand only the mitochondrion is lost.As the oxidative damage of the mitochondrion increases, molecules such as cytochrome C may bereleased 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 ActivationWhen the mitochondrial damage is too extensive and cannot be repaired by Bcl-2 protein, caspase areactivated, leading to apoptosis. Caspases are a family of proteases (executioner proteins) that orchestrateapoptosis. Fourteen mammalian caspases have been identified, three of which (caspase-3, -6, and -7) arethought to coordinate the execution phase of the neuron.
Biological Markers of Neurodegenerative DiseasesUNWANTED APOPTOSIS: in neurodegenerative diseases such as Alzheimer’s disease, caspase 3 isconstantly elevated because of the ongoing active cell death, also the BAX/Bcl-2 ratio is elevated becausecells are prone to apoptosis.FAILURE OF APOPTOSIS: in cancer caspase 3 and the BAX/Bcl-2 ratio are low because cancer cells areresistant 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 3activation (execution phase). There is no active cell death in schizophrenia, yet there is evidence ofneuronal atrophy and synaptic loss in some areas of the brain.These changes could reflect either a pathophysiological failure to mount an effective response to anapoptotic insult, or an apoptotic compensatory response to an earlier insult.Unable to solve this dilemma, scientists proposed the localized apoptosis theory. It claims that theneurons themselves do not die, but the dendrites and synapses undergo autophagy (inadequately termedlocal apoptosis). Final stage of a white blood cell apoptosisIn conclusion: Most neurodegenerative diseases commence with the imbalance between pro-survival andpro-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 Alzheimers disease. For this reasonthe interest in caspases as potential therapeutic targets for neurodegenerative diseases, excludingschizophrenia, has constantly increased since the mid-1990s when they were first discovered.
Some Psychotropic Drugs Protect the Mitochondrion by Increasing Bcl-2During the past few years research has focused on developing neuroprotective agents for the therapy ofvarious 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 associatedwith neuronal atrophy and cell loss in some areas of the brain.Lithium and Valproate as a Neuroprotective AgentsIn a recent clinical study, researchers found that dysfunctional autophagy was the final common pathwayin the genesis of Amyotrophic Lateral Sclerosis(ALS).Lithium administration slowed the progression of ALS in human patients. It is believed that lithiumdesensitizes brain mitochondria to calcium, and diminishes cytochrome c release, preventing initiation ofapoptosis.Another recent study showed that chronic lithium treatment markedly increased the levels of the majorneuroprotective 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 ofAlzheimer’s disease, Huntington’s disease, Parkinsons’s disease, retinal degeneration, spinal cord injuryand HIV infection.Valporic acid was also found to be neuroprotective by increasing the level of Bcl-2 protein as well..Valproate and lithium were found to increase Bcl-2 in the frontal cortex, the striatum and hippocampus.
Antidepressants as Neuroprotective AgentsThe SSRI fluoxetine was found to upregulate Bcl-2 in the hippocampus, but not in the frontal cortex orthe striatum. SSRIs also upregulate BDNF.Pramipexole as Neuroprotective AgentPramipexole is the presynaptic dopamine agonist which is FDA approved for the treatment of Parkinson’sdisease and restless leg syndrome. Pramipexole upregulates Bcl-2 protein in different areas of the brain.Pramipexole also upregulates BDNF.Olanzapine and Clozapine as Neuroprotective AgentsIn animal models, administration of Olanzapine or Clozapine upregulated Bcl-2 in the frontal cortex andthe hippocampus (Hammonds 2009; also Bai O, Zhang 2004). Also in human neuroblastoma, clozapineor olanzapine, but not haloperidol, prevented the decrease in Bcl-2 (Kim NR, 2008)Neuroprotective Non-Psychotropic DrugsMany non-psychotropic drugs were also found to have neuroprotective action. They will be mentionedhere briefly, but discussed in more detail in future essays.Pregnenolone and DHEA,EstrogenErythropoietinRasagilineS-AdenosylmethionineSirtuinsPiracetamL-TheanineRetinoidsADONIS SFERA, MD