Functional Neurology: Nrf2 Activation for Neurological Diseases

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Nerve Injury, Neuropathy

Neurological diseases, including well-known neurodegenerative disorders like Alzheimer’s disease (AD) and Parkinson’s disease (PD) as well as other rare health issues, such as Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people worldwide. Unfortunately, these are estimated to increase due to the aging population. Currently, there is no treatment available for any neurodegenerative disorder. Treatments for symptoms are available for several neurological diseases, such as PD and HD, but the therapeutic benefits are limited. Although the causes and symptoms for these health issues are different for each neurodegenerative disorders, their molecular pathogeneses share common underlying factors and characteristics, including excessive levels of reactive oxygen species (ROS), mainly due to mitochondrial impairment, neuroinflammation, and disturbances in protein homeostasis (proteostasis). This increases the possibility of developing a universal treatment that will focus on targeting the common triggers of neurological diseases. �

Nrf2 Activation Pathways and the Human Brain

The transcription factor, Nrf2, regulates the main endogenous defense mechanism against oxidative and xenobiotic stress and inflammation. Nrf2 also plays a fundamental role in the management of mitochondrial function and cellular proteostasis, which suggests the possible benefits of Nrf2 to control neurodegenerative disorders. When under stress, Nrf2 activates the transcriptional upregulation of a large network of cytoprotective genes that allow adaptation and survival. The levels and activity of Nrf2 are controlled through ubiquitination and proteasomal degradation mediated by several ubiquitin ligase systems, including Keap1-Cul3/Rbx1, ?-TrCP-Cul1, and Hrd1. Keap1 is the most well understood key regulator of Nrf2. �

Keap1 functions as a primary sensor for electrophiles and oxidants, which chemically change certain cysteines in Keap1, leading to conformational changes that protect Nrf2 from Keap1-associated degradation. Subsequently, Nrf2 will accumulate and then translocate to the nucleus where it binds as a heterodimer with a small Maf transcription factor to antioxidant response elements in the promoter of its target genes to activate the expression of a large network of detoxification, antioxidant, and anti-inflammatory genes as well as other genes involved in the clearance of damaged proteins. Of particular interest is also the upregulation of genes responsible in the biosynthesis and the regeneration of glutathione (GSH), a major intracellular antioxidant. Moreover, Nrf2 also suppresses proinflammatory responses through transcriptional repression and it is involved in the regulation of mitochondrial function. Keap1 and p62/SQSTM1 are Nrf2-associated proteins and main regulators of negative and positive feedback loop mechanisms. In addition, p62 targets Keap1 for selective degradation through autophagy, therefore contributing to the sustained Nrf2 activation response. �

Aging has been associated with the increase in ROS and chronic inflammation, which suggests a loss of adaptability and/or impairment of Nrf2 signaling, which are particularly pronounced in age-dependent neurodegenerative disorders. Surprisingly, rare mutations in SQSTM1 can cause susceptibility to the human neurodegenerative disorder, ALS as well as frontotemporal lobar degeneration, and are associated with muted Nrf2 activation responses in clinical trials. Research studies suggest a reciprocal correlation and show negative effects of mutant disease-related proteins on Nrf2 signaling, thus suggesting the inhibition of the Nrf2 pathway as a possible mechanism underlying neurodegeneration and health issues. �

Nrf2 Activation for Neurodegenerative Disorders

ALS, an adult-onset neurodegenerative disorder caused by the selective death of motor neurons in the brain and spinal cord, is commonly characterized by progressive muscle weakness and atrophy which is generally considered to be fatal, typically within 5 years of diagnosis. ALS has a predominant sporadic ALS form with no apparent genetic component, however, approximately 5 to 10 percent of cases show an autosomal dominant inheritance pattern or familial form of the disease, known as fALS, with is known to cause gene mutations. The symptoms of sporadic ALS and familial ALS are similar, which suggests the involvement of common pathogenic mechanisms, including oxidative stress and neuroinflammation. �

Research studies show that oxidative stress and neuroinflammation should be the key therapeutic targets of Nrf2 signaling in ALS. Genetic research studies in ALS mouse models have shown a considerable therapeutic effect of increased Nrf2 levels in astrocytes, the main GSH producers for neurons. Furthermore, Nrf2 signaling is fundamental for controlling neuroinflammation in ALS through the management of the effects of activated microglial cells on overall neuronal survival. Consistent with the therapeutic potential of Nrf2 signaling, treatment with small molecule activators, including the extremely potent cyanoenone triterpenoids, has ultimately shown efficacy in research study mouse ALS models. �

The neuroprotective potential of Nrf2 activation has been evaluated in experiments utilizing genetic mouse HD models. HD is an autosomal dominant and highly penetrant neurodegenerative disorder, which results from the pathological expansion of a trinucleotide CAG repeats encoding polyglutamines in HTT protein. Brains from patients with HD usually show marked striatal and cortical atrophy at the time of diagnosis. Once motor or other symptoms become apparent, generally throughout midlife, the affected individuals become increasingly disabled over the course of 15 to 25 years before eventually succumbing to the effects of severe physical and mental deterioration, according to evidence from research studies. �

Complex pathogenic mechanisms have been shown in HD, however, excessive oxidative stress has been recognized as a fundamental driver of pathology. The harmful role of oxidative stress has been described in both HD patients and in experimental clinical trial models and it is potentially due to the neuronal sensitivity of an excess in ROS. The levels of several Nrf2-dependent antioxidant proteins, including glutathione peroxidases, catalase, and superoxide dismutase 1, are increased in human HD brains as compared with non-disease controls, suggesting a partial activation of Nrf2 defense signaling yet insufficient enough to block progressive neurodegeneration. Pharmacological activation of Nrf2 results in the broad antioxidant effects of HD in mouse brains and ameliorates the neurological phenotype. Increased expression of several key inflammatory mediators has been shown in the blood, the striatum, the cortex, and the cerebellum from postmortem patient HD tissues, however, neuroinflammation in HD patients seems to be less pronounced than in ALS or PD patients. �

Neurological Disease Treatment with Nrf2 Activation

Finally, the neurological phenotype of the most common neurological disease and neurodegenerative disorder, PD, can be challenged by Nrf2 activation. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the profound reduction of dopamine in the striatum. Currently available dopaminergic treatments offer relief from several symptoms but these only address the motor manifestations. Multiple genetic and environmental factors have been suggested in the etiology of PD, however, like ALS, the majority of the clinical cases are sporadic. The discovery that the environmental neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes Parkinson’s disease in humans, led to the development of the MPTP mouse model of disease, which to date, remains one of the most highly utilized animal models of sporadic PD, including the evaluation of drug efficiency. Nrf2 activators showed neuroprotective effects in MPTP mice, which are associated with a reduction of oxidative damage and neuroinflammation. The identification of causative mutations in SNCA, the gene encoding ?-synuclein (aSyn), developed genetic mouse PD models, in which daily oral delivery of the Nrf2 activator dimethyl fumarate (DMF) protected nigral dopaminergic neurons against aSyn toxicity. �

Although oxidative stress and neuroinflammation are pathological hallmarks of AD, a therapeutic role of Nrf2 signaling has developed more slowly, perhaps due to the complexity of disease pathogenesis and readouts of efficiency. Nonetheless, there is a number of recent research studies that demonstrate the efficiency of Nrf2 activators in AD mouse models. � DMF, a U.S. FDA-approved drug (Tecfidera, Biogen-Idec) for the treatment of relapsing multiple sclerosis, activates Nrf2 through the regulation of the Keap1 sensor. DMF is of seemingly low potency and specificity, which prevents neurodegeneration. Drug-like molecules with a similar mechanism of action or with the ability of direct interference with the Keap1/Nrf2 interaction are emerging. The data demonstrate the feasibility to develop Nrf2 activators for treatment. �

In summary, although the causes and symptoms of neurological diseases are different, neurodegenerative disorders share similar molecular mechanisms, which could be regulated and managed with Nrf2 activators. Moreover, targeting Nrf2 signaling may offer a safe and effective treatment approach for a variety of these health issues. Because pharmacological Nrf2 activation targets the broad mechanisms of these health issues, all neurodegenerative conditions would be eligible for treatment. Furthermore, the main goal is to develop noninvasive oral treatment(s) for patients under the supervision of healthcare professionals, which targets both sporadic and familial patients. – Dr. Alex Jimenez D.C., C.C.S.T. Insight

Neurotransmitter Assessment Form

The following Neurotransmitter Assessment Form can be filled out and presented to Dr. Alex Jimenez. Symptoms listed on this form are not intended to be utilized as a diagnosis of any type of disease, condition, or any other type of health issue. �

Neurological diseases, including well-known neurodegenerative disorders like Alzheimer’s disease (AD) and Parkinson’s disease (PD) as well as other rare health issues, such as Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people worldwide. Unfortunately, these are estimated to increase due to the aging population. Currently, there is no treatment available for any neurodegenerative disorder. Treatments for symptoms are available for several neurological diseases, such as PD and HD, but the therapeutic benefits are limited. Although the causes and symptoms for these health issues are different for each neurodegenerative disorders, their molecular pathogeneses share common underlying factors and characteristics, including excessive levels of reactive oxygen species (ROS), mainly due to mitochondrial impairment, neuroinflammation, and disturbances in protein homeostasis (proteostasis). This increases the possibility of developing a universal treatment that will focus on targeting the common triggers of neurological diseases. �

The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues or functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �

Curated by Dr. Alex Jimenez �

References: �

• Dinkova-Kostova, Albena T, et al. �Activation of Nrf2 Signaling as a Common Treatment of Neurodegenerative Diseases.� Activation of Nrf2 Signaling as a Common Treatment of Neurodegenerative Diseases | Neurodegenerative Disease Management, 23 May 2017, www.futuremedicine.com/doi/full/10.2217/nmt-2017-0011#.

Additional Topic Discussion: Chronic Pain

Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.

Neural Zoomer Plus for Neurological Disease

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Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural Zoomer^TM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural Zoomer^TM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural Zoomer^TM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �

Food Sensitivity for the IgG & IgA Immune Response

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Dr. Alex Jimenez utilizes a series of tests to help evaluate health issues associated with food sensitivities. The Food Sensitivity Zoomer^TM is an array of 180 commonly consumed food antigens that offers very specific antibody-to-antigen recognition. This panel measures an individual�s IgG and IgA sensitivity to food antigens. Being able to test IgA antibodies provides additional information to foods that may be causing mucosal damage. Additionally, this test is ideal for patients who might be suffering from delayed reactions to certain foods. Utilizing an antibody-based food sensitivity test can help prioritize the necessary foods to eliminate and create a customized diet plan around the patient�s specific needs. �

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