How CoQ10 Protects Brain Cells
Conclusion of a 3-part Series on Cellular Bioenergetics and CoQ10October 2001
Alzheimer’s disease is the most common adult-onset dementia. In recent years researchers have discovered many of the mechanisms involved in the disease, but we cannot yet clearly separate causes from effects in this complex pathology. The theories we discuss are necessarily quite speculative.
The main effects of Alzheimer’s disease on brain tissue are extensive neuron loss and insoluble fibrous deposits called senile plaques and neurofibrillary tangles. The core of the plaques is a toxic protein, amyloid-beta, that assails cells on several fronts. Amyloid-beta generates oxidative stress, damages mitochondrial DNA, impairs cellular bioenergetics, and alters proteins so as to form neurofibrillary tangles.
A number of recent studies have found that the degree of disability in Alzheimer’s disease patients correlates with impairment of energy metabolism in the brain. In fact, a new study suggests that cellular energy production may be a better indicator than senile plaques of Alzheimer’s disease severity. This study of Alzheimer’s patients in a nursing home found that their degree of clinical disability correlated with a mitochondrial abnormality involved in cellular respiration, but did not correlate with the density of senile plaques.
Together with amyloid-beta, a potent free radical called peroxynitrite oxidizes lipids in neuronal membranes. This generates the highly toxic byproduct HNE that is found in excess in multiple regions of the Alzheimer’s disease brain. HNE kills brain cells directly, and also indirectly by making them more vulnerable to excitotoxicity. As we have seen, the co-antioxidants coQ10 and vitamin E protect cell membranes from lipid peroxidation, and coQ10 has been found to reduce peroxynitrite damage and HNE formation in the bloodstream.
We do not know whether Alzheimer’s disease arises from a single underlying cause. An interesting multiple-factor theory was published in the journal Gerontology (Ying W, 1997). According to this theory, Alzheimer’s disease develops from four causes: imbalances in APP (amyloid precursor protein) and calcium, oxidative damage and bioenergetic deficit. The author cites studies showing that each of the factors reinforces and is reinforced by each of the other factors. This “deleterious network,” as the author calls it, potentially fits the therapeutic profile of coQ10. However, coQ10 has never been included in a clinical trial for Alzheimer’s disease. The reasons for this may not be scientific ones, as discussed at the end of this article.
While we do not yet know whether coQ10 has a place in Alzheimer’s disease prevention or therapy, a synthetic analogue of the coQ10 family called idebedone has yielded impressive results in several European and Japanese clinical trials for Alzheimer’s disease and other dementias. According to the authors of a German study of the drug, idebedone "acts on the brain by increasing the cerebral energy supply and by protecting the cell membranes against lipid peroxidation" (Weyer G et al., 1997). This study tested two dosages of idebedone on patients suffering from mild to moderate Alzheimer’s disease. A total of 247 patients completed the well-designed six month long clinical trial.
Patients were evaluated on the international Alzheimer’s Disease Assessment Scale (ADAS). On average, patients taking the higher dose of idebedone improved by 2.3 points on the 120 point scale as a result of treatment. The more severe the disease was at the beginning of the study, the more the patient improved, on average. Those patients who began the study with an ADAS score of at least 20 points showed gains averaging 4.1 points compared to placebo. The largest gains were on cognitive tasks, reaching 6.9 points compared to placebo on the 50 point ADAS Cognitive Scale in patients with the most severe disease (total ADAS score of at least 50 points) taking the higher dose. Of course the results of this study are not transferable to coQ10. The drug idebedone is not available in the U.S.
In the next section we turn our attention from chronic neurodegenerative diseases to the sudden attacks, loosely called strokes, seen in cerebrovascular disease.
The circulation of blood through the brain delivers a constant supply of oxygen, glucose and nutrients to brain cells. When the steady flow of blood through a portion of brain tissue ceases—as from a clot or hemorrhage—metabolism rapidly fails in brain cells. After a few minutes without blood, neurons suffer irreversible injury (see sidebar “The Ischemic Cascade”).
However, a stroke does not cut off blood supply uniformly. Rather, circulation falls off toward the core of the affected area, where little or no blood may flow. Cells in the core tend to die quickly through necrosis. These cells break apart, spilling their contents into nearby tissue. The mystery of stroke is how and why cells in the surrounding area die off hours or days later. This delayed, or secondary, brain damage is now considered potentially preventable. A growing body of research suggests that the focus of both primary and secondary stroke damage—and potential stroke therapy—lies in the mitochondria.
While the brain consumes a disproportionate share of the body’s circulation (14%) and oxygen (20%), its energy reserves are very small, especially considering the brain’s extraordinary energy demand. Other cells with high energy demand, such as muscle cells, are much better equipped to generate energy from stored glucose. The brain’s energy stores can sustain metabolism for only about one minute. Hence neurons are particularly vulnerable when cellular respiration fails during ischemia (reduced blood flow). It is no wonder that the mitochondria are considered “subcellular targets” of ischemic injury in the brain. As summarized in one research paper (Veitch K et al., 1992):
Indeed, the transition from reversible to irreversible ischemia has been suggested to depend on the functional state of mitochondria… restoration of oxidative metabolism [the energy-producing cellular respiration process] determines functional recovery.
Brain mitochondria, with their special sensitivity to reduced blood flow, exhibit the first signs of brain injury during ischemia. Even a moderate reduction of cerebral blood flow substantially impairs cellular respiratory activity. Injury to mitochondria during and after a stroke brings manifold consequences. These include metabolic failure, oxidative stress, calcium dysregulation, increased excitotoxicity and promotion of programmed cell death. The effects of mitochondrial impairment cause further mitochondrial impairment, generating “a vicious cycle of subcellular injury and abnormal intracellular conditions” in the aftermath of a stroke (Fiskum G et al., 1999).
Mitochondria may actually suffer greater injury when blood flow is reduced than when it stops completely. This is because complete cessation of blood flow also cuts off the supply of oxygen, thereby reducing oxidative stress. When blood flow is merely reduced, oxygen continues to flow, generating free radicals on top of those spewed out by stroke-impaired cellular respiration. These radicals attack mitochondrial lipids, DNA, and respiratory chain components. The return of blood and oxygen to the affected area likewise does greater injury to the cellular respiratory chain after a reduction in blood flow than after a complete cutoff.
The scope of the neurological impairment caused by a stroke depends upon secondary brain damage, also called delayed neuronal death. Research suggests that secondary brain damage follows from secondary mitochondrial and bioenergetic failure after blood flow resumes.
The question of whether secondary brain damage occurs through necrosis or programmed cell death—or something in between—is one of the most hotly debated issues in medical research today. Much recent evidence points to programmed cell death as a major factor in delayed neuronal death. While this cellular suicide program disposes of cells in a neat, orderly way, stroke may trigger it accidentally. Mitochondrial conditions during and after ischemia appear to set off the suicide program in otherwise viable cells. Whatever the mode of cell death, similar processes of cellular energy failure, consequent calcium overload and excitotoxicity, oxidative stress and opening of the mitochondrial megachannel may unfold.
Measures that support cellular energy production and antioxidant defense while protecting against excitotoxic damage and programmed cell death might help protect this tissue. CoQ10’s properties would appear to lend themselves to this, and animal experiments with CoQ10 support this hypothesis. Japanese scientists tested CoQ10 in a standard animal model of human stroke. They induced strokes in Mongolian gerbils by blocking the carotid artery. The gerbils that developed stroke symptoms were either left untreated, or treated after four hours with subcutaneous pellets of CoQ10 or one of two drugs. The untreated gerbils lived 17 hours on average, and all were dead after 28 hours. In contrast to this, nearly half (45%) of the gerbils treated with CoQ10 survived until the end of the experiment four weeks later. The two drugs tested were far less successful than CoQ10 in prolonging the lives of the gerbils following stroke.