Glaucoma

Tetrahydrocannabinol and novel mechanisms in reducing intraocular pressure in glaucoma

Virginia Thornley, M.D.,  Neurologist, Epileptologist

February 28, 2018

Introduction

The endocannabinoid system is composed of 3 systems: (the cannabinoid receptors, (2) endocannabinoid transportation system and (3) enzymes that break down the ligands. Two endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) are elevated in response to a wide variety of pathological events. This suggests a compensatory response of endocannabinoids in response to damage or pathology within the system (3). Activation of the endocannabinoid system appears to correlate with cell repair and survival. The G-receptors discovered called CB1 and CB2 trigger transducer signal cascades and influence peripheral central cell functions.

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Cannabidiol in glaucoma

Cannabidiol is becoming a topic of hot debate in pain, anti-tumor effects, epilepsy and in glaucoma.  Glaucoma can result in increased intraocular pressure resulting in damage to the optic nerve at the retinal attachment. There is the narrowing of the visual field and eventual blindness through retinal damage. and blindness. Cannabinoid receptors have been found in the ocular cells leading to speculation of benefits of cannabinoids in glaucoma.

In one study of 32 different types of cannabinoids, it was found that certain derivatives of delta 9THC and delta 8THC were more effective at lowering intraocular pressure in glaucoma than the parent derivative cannabidiol (1).

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Mechanism for treating glaucoma

One possible mechanism in ameliorating intraocular pressure is by suppressing N-methyl D-aspartate or NMDA receptor excitability, increasing neural vasculature circulation, suppressing apoptosis and damaging free radicals. Separation of the novels effects appears possible from the toxic side effect through novel technique (2).

Involvement of cannabinoid and their receptors in retinal cells have been well documented in fish cells to primates and more recently in neurodegeneration and neuroprotection. There is a fine balance of biosynthetic and degrading enzymes that influence endocannabinoids and exert neuroprotection during trauma, inflammation, ischemia and neurotoxicity found in brain damage (4).

In addition, in one study in 21 dogs, when 2% of tetrahydrocannabinol was applied, the intraocular pressure was reduced (5) which was found statistically significant.

 

https://neurologybuzz.com/

Introduction/Disclaimer

About

References

  1. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
  2. Jarvinen, T., “Cannabinoids in treatment of glaucoma,” 2002, Aug., 95(2):203-20.
  3.  Karanian, et al, “Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states,” Current Molecular Med., 2006, Sep., 6(6):677-84.
  4.  Rapino, et al, “Neuroprotection by endocannabinoids in glaucoma and retinal neurodegenerative diseases,” Current Neuropharmacology, 2017, Jul., doi:10.2174 (Epub ahead of print)
  5. Fischer, et al, “Effects of a topically applied 2% delta-9-tetrahydrocannabinol ophthalmic solution on intraocular pressure and aqueous humor flow rate in clinically normal dogs,” American J. Vet. Res., 2013, Feb., 74(2):275-80.

 

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Parkinson's disease

Parkinson’s disease: cannabidiol, tetrahydrocannabinol, CB1 and CB2 receptors and anti-oxidant properties in neuroprotection 

Virginia Thornley, M.D., Neurologist, Epileptologist

March 2, 2018

Introduction

Cannabinoids are compounds part of the endocannabinoid pathways found inherent to the brain comprising of endocannabinoids, transporters and receptors. Cannabidiol is a mimetic for 2-2-arachidonyl (2-AG) and tetrahydrocannabinol is a mimetic for Anandamide (AEA). 2 receptors for cannabidiol are found in the brain CB1 mainly seen in the basal ganglia and limbic system and CB2 found in the immune system. The receptors are G-coupled and suppress adenylate.

With Parkinson’s disease, there is reduced production of dopamine in the substantia nigra which means there is less inhibitory effect on the basal ganglia resulting in increased acetylcholine from the basal ganglia which results in tremors. Cannabinoids appear to influence the neurotransmitter system within the brain and have found to be beneficial in movement disorders in the animal model.

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Mechanisms of cannabidiol and THC in Parkinson’s disease animal model

There are more CB1 receptors in brains with Parkinson’s disease and the MPTP model, likely a result of less inhibition from the dopaminergic substances and a compensatory mechanism in the brain. There are more CB1 receptors possibly as a response to the reduced dopaminergic effect (2). It was postulated that CB1 agonists may exert a neuroprotective effect against 3 toxins paraquat, MPP+, and lactasyn. However, using experimental techniques, the neuroprotection from 9THC is likely not related to the CB1 receptor. Evidence supports that the neuroprotection afforded by THC may be related to its antioxidant properties. This may be through the effects of PPARy or the peroxisome proliferator-activated receptor gamma.

Other studies propose that the neuroprotective effects of cannabidiol and THC are independent of the CB1 receptor and related to the antioxidant effects. It was found that CB2 receptor activation may slow the progression of neurodegeneration on Parkinson’s disease. CB2 receptors are found naturally in the cells but appear upregulated in diseased cells such as in Parkinson’s disease, suggesting an endogenous protective effect. It may exert effects by reducing proinflammatory responses. Activation of CB2 receptors may represent a promising role of CB2 receptors in the treatment of Parkinson’s disease (3).

Cannabidiol and clinical studies in Parkinson’s disease

In one study of 119 patients, cannabidiol was given at 75mg/day or 300mg/day. Patients were assessed using variables of motor symptoms according to the UPDRS, well-being and life quality (PDQ-39) and neuroprotective effects.

One week before the trial and in the last week of treatment participants were assessed in respect to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and H(1)-MRS). They found no difference in motor assessment and neuroprotection but the quality of life seemed to improve in the group taking 300mg compared with placebo(1).

 

Medical marijuana has been demonstrated to be effective in bradykinesia, tremors seen in the Parkinson’s disease. Cannabinoids have been found effective in psychosis and sleep disorders seen in Parkinson’s disease(4).

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Introduction/Disclaimer

About

References

  1. Chagas, et al, “Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial,” Journal of Psychopharmacology, 2014, Nov., 28(110):1088-1098.
  2.  Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
  3. Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
  4. Babyeva, et al, “Marijuana compounds: a non-conventional approach to Parkinson’s disease therapy,” Parkinson’s Disease, 2016:1279042.
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Peripheral neuropathy

On pluripotent stem cell research chemotherapy-induced peripheral neuropathy

Virginia Thornley, M.D., Neurologist, Epileptologist

March 1, 2018

Introduction

As more and more survivors of cancer grow in number, there is increasing interest in treatments for chemotherapy-induced toxicity. Chemotherapy-induced peripheral neuropathies are one of the most common neurotoxic side effects prevalent in cancer survivors. Attention is drawn to alternative treatments such as stem cell research as at times, this condition may be resistant to treatment with conventional agents.

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Common chemotherapeutic agents that cause neuropathy

Some of the most common chemotherapeutic agents that cause peripheral neuropathy include vincristine, oxaliplatin, cisplatin, paclitaxel. The sites most prevalent with neurotoxic effects include the dorsal root ganglion, peripheral nerves, satellite cells and Schwann cells as well as glial cells in the spinal cord.

Some mechanisms that are proposed that cause neural damage include glutamate activation, increased intracellular oxygen changes, DNA damage, altered cell repair, alteration in ion channels, change in mitochondrial metabolism and MAP kinase activation.

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Role of stem cell in chemotherapy-induced peripheral neuropathy and other novel treatment approaches

In chemotherapy for colon cancer, oxaliplatin can cause chemo-induced peripheral neuropathy in 50% of patients. In one study, pain relieving qualities of mesenchymal stem cells were studied. Rat adipose stem cells were applied to rats with chemotherapy-induced peripheral neuropathy in one animal model. An IV injection of rat adipose stem cell injected into the rate of neuropathy revealed a reduced hypersensitivity to the noxious effects. Repeated injections every 5 days produced the same results. VEGF was noted to be upregulated or vascular endothelial growth factor. When a monoclonal antibody used against this VEGF was applied there was reduced pain, suggesting a role of VEGF in pain. Adult adipose mesenchymal stem cell may represent a novel approach to alleviating pain from chemotherapy-induced peripheral neuropathy. This rat model also elucidated the role an antibody against VEGF can play in the treatment of peripheral neuropathy caused by chemotherapy.

Pain might also be influenced by increased gap junction coupling during chemotherapy. In one study, using a gap coupling blocker, the pain was alleviated in chemotherapy-induced peripheral neuropathy in mice producing an analgesic effect(3).

 

Reference:

  1. Di Cesare, et al, “Adipose-derived stem cells decrease pain in a  rat model of oxaliplatin-induced neuropathy: role of VEGF-A modulation,” Neuropharmacology, 2018, Mar., 15; 131:166-175.
  2. Carozzi, et al, “Chemotherapy-induced neuropathy: what do we know now?” Neuroscience Letter, 2015, Jun., 2(596):90-107.
  3. Warwick, et al, “The contribution of satellite glial cells to chemotherapy-induced neuropathic pain,” European Journal of Pain, 2013, Apr., 17(4):571-80.
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Amyotrophic lateral sclerosis

Pluripotent stem cell research and amyotrophic lateral sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist

March 1, 2108

Introduction

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease resulting in muscle weakness and respiratory failure. The mechanisms still remain unclear and there is no cure. Recent interest is growing in stem cell research as a novel treatment for ALS.

Stem cells and ALS

Induced pluripotent stem cells have been studied to identify the mechanism underlying ALS and develop treatments using these models. Using stem cells it is possible to grow a disease in a dish and study the mechanisms. The cells are generated from healthy subjects and patients with neurodegenerative disorders cultivating them to produce different types of neurons. CNS neurons are separated from peripheral neurons. Neurotrophins and other factors are used to accomplish this. It is important that these neurons can produce synaptic connections. In some studies, only a low number will differentiate into the neurons with the desired morphologic features and have the desired physiologic functions. The use of pluripotent stem cells is an important landmark in research because it allows researchers to study the disease of ALS with pluripotent cells capable of differentiating into different types of neurons including upper motor neuron, lower motor neuron cells, astrocytes, oligodendrocytes and allows researchers to understand the different dynamics between the cells in the diseased state (2).

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Potential mechanisms of stem cell treatment in ALS

One mechanism is by changing the somatic cells into neuron-like cells. There are now established ways of forcing transcription factors into changing somatic cells into neuron-like cells expressing neuron-specific proteins. The majority studied had excitatory traits. The most important feature is being able to propagate action potentials and developing dendrites.There are some reports of fibroblasts transforming into GABAergic cells using neurotrophins. Reprogrammed cells could convert into neurons, astrocytes and oligodendrocytes. Some cells cannot convert using genomic insertion which may be a barrier.

Induced pluripotent stem cells can be produced from the patient’s own stem cells. Direct conversion of somatic cells into neural cells is an alternative (1).

Introduction/Disclaimer

References

  1. Csobonyeiova, et al, “Induced Pluripotent Stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis, ” Journal of Physiology and Pharmacology, 2017, 68(5):649-657.
  2. Guo, et al, “Current advances and limitations in modeling ALS/FTD in a dish using induced pluripotent stem cells,” front. Neuroscience, 2017, Dec., https://doi.org/10.3389/fnin.2017.00671
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Glaucoma, Uncategorized

9Tetrahydrocannabinol and novel mechanisms in reducing intraocular pressure in glaucoma

Virginia Thornley, M.D.,  Neurologist, Epileptologist

February 28, 2018

Introduction

The endocannabinoid system is composed of 3 systems: (the cannabinoid receptors, (2) endocannabinoid transportation system and (3) enzymes that break down the ligands. Two endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) are elevated in response to a wide variety of pathological events. This suggests a compensatory response of endocannabinoids in response to damage or pathology within the system (3). Activation of the endocannabinoid system appears to correlate with cell repair and survival. The G-receptors discovered called CB1 and CB2 trigger transducer signal cascades and influence peripheral central cell functions.

13909252_10154408552708841_6462398358021475581_o

Cannabidiol in glaucoma

Cannabidiol is becoming a topic of hot debate in pain, anti-tumor effects, epilepsy and in glaucoma.  Glaucoma can result in increased intraocular pressure resulting in damage to the optic nerve at the retinal attachment. There is the narrowing of the visual field and eventual blindness through retinal damage. Cannabinoid receptors have been found in the ocular cells leading to speculation of benefits of cannabinoids in glaucoma.

Mechanism for treating glaucoma

One possible mechanism in ameliorating intraocular pressure is by suppressing N-methyl D-aspartate or NMDA receptor excitability, increasing neural vasculature circulation, suppressing apoptosis and damaging free radicals. Separation of the novels effects appears possible from the toxic side effect through novel technique (2).

Involvement of cannabinoid and their receptors in retinal cells have been well documented in fish cells to primates and more recently in neurodegeneration and neuroprotection. There is a fine balance of biosynthetic and degrading enzymes that influence endocannabinoids and exert neuroprotection during trauma, inflammation, ischemia, and neurotoxicity found in brain damage (4).

THC studies and glaucoma

In a rabbit model, 9THC showed improved penetration to the anterior chamber with reduction of intraocular pressure using a prodrug. THC is an established neuroprotectant and has the possibility of being an effective IOP lowering agent. THC and THC-Val-HS reached the retina choroid(5).

 

In one study of 32 different types of cannabinoids, it was found that certain derivatives of delta 9THC and delta 8THC were more effective at lowering intraocular pressure in glaucoma than the parent derivative cannabidiol (1).

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Introduction/Disclaimer

https://neurologybuzz.com/

About

 

References

  1. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
  2. Jarvinen, T., “Cannabinoids in treatment of glaucoma,” 2002, Aug., 95(2):203-20.
  3.  Karanian, et al, “Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states,” Current Molecular Med., 2006, Sep., 6(6):677-84.
  4.  Rapino, et al, “Neuroprotection by endocannabinoids in glaucoma and retinal neurodegenerative diseases,” Current Neuropharmacology, 2017, Jul., doi:10.2174 (Epub ahead of print)
  5.  Goutham, et al, ” Development of a 9tetrahydrocannabidiol amino acid dicarboxylate prodrug with improved ocular bioavailablity,” Investigative Ophthalmology and Visual Science, 2017, Apr., 58(4):2167-2179.

 

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Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis: how diet may be associated with better outcome and management

Virginia Thornley, M.D., Neurologist, Epileptologist

February 27, 2018

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder resulting in muscle weakness, atrophy and eventual respiratory failure. It involves mitochondrial dysfunction, oxidative stress, apoptosis, neural inflammation, metallic accumulation, decreased trophic factors, glutamate activation, and superoxide dismutase-1. There is a growing interest in the role of diet in the natural progression and treatment. Risk of ALS may increase with increased intake of macronutrients such as carbohydrates, glutamate, and fat and a reduced intake of micronutrients such as carotenoids, fruits and vegetables, polyunsaturated fatty acids and Vitamin E. Oxidative stress may also increase the risk of ALS.

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Good food versus bad food in ALS

In one study of 306 patients in over 16 ALS centers, milk and lunchmeat seemed to correlate with a negative ALS function using the ALSFRS score (ALS functional rating score) or the percentage FVC (forced vital capacity) for the outcome. Milk and lunchmeat are associated with higher fat and potentially promote oxidative stress. It studied foods that were considered good (calcium, iron, potassium, iron, thiamine, riboflavin, niacin, zinc, selenium, vitamins C, D, E, K, and B6, magnesium, and glutathione) versus bad(phosphorus, caffeine, food-producing high glycolic index). The components of the good food groups had eggs, poultry, fish, beneficial oils and vegetables and are often associated with anti-oxidants and a healthy diet. The study only provides an association not a causation of good food towards a better outcome. Food high in fiber, carotenoids, and antioxidants provided a better outcome(1).

Another study noted that patients with the lowest score of ALSFRS appear in those with the lowest intake of vegetables, grains, oils, and seasonings (3).

Novel treatments using diet

In one study using a high caloric diet and an MAO-inhibitor/iron-chelating compound  M30 in the superoxide dismutase-1 mouse model, results showed neuroprotection involving motor function and increased survival in the SOD-1 G93A transgenic mouse model. The M3 and CED (high caloric diet) resulted in increased mitochondrial biogenesis and metabolic regulators. A combination of novel approaches may help treat this condition (2).

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1. Nieves, et al, “Association between dietary intake and function in Amyotrophic lateral sclerosis, ” 2016, Dec., 73 (12)1425-1432.

2. Golko-Perez, et al, “Additive Neuroprotective effects of the multifunctional iron chelator M30 with enriched diet in a mouse model of amyotrophic lateral sclerosis,” Neurotoxicity Research, 2016, Feb., 29(2):208-217.

3. Park, et al, “Association between nutritional status and disease severity using amyotrophic lateral sclerosis (ALS) functioning rating scale in ALS patients”Nutrition, 2015, Nov.-Dec., 31(11-12):1362-7.

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Epilepsy

Ketogenic diet and its variants modifed Atkins diet, low glycemic index treatment: effectiveness, side effect profile in patients with epilepsy and incidental weight loss

Virginia Thornley, M.D., Neurologist, Epileptologist, February 26, 2018

Doctors first took notice of the ketogenic diet working in patients with epilepsy in the 1920’s. But the exact mechanism remains unclear. One study elucidated that the ketone bodies are one of the reasons why the ketogenic diet works in patients with epilepsy. Ketosis occurs during a natural fasting state. In the ketogenic diet using high fat, the by-products of beta-oxidation of fatty acids which are beta-hydroxyacetate and acetoacetate in the blood do not correlate with patients who are doing better. Medium chain triglyceride fatty acids, which are a part of a variation of the ketogenic diet, are shown to suppress the AMPA receptors which subserve the excitatory neurotransmitter glutamate and may change energy use of the cell through mitochondrial processes (1).

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Ketogenic diet and adverse effects

Some patients have difficulty adhering to the diet which makes it difficult to use. Common side effects because of the high-fat content are diarrhea, constipation, nausea, transient increase in lipemic values. Variations of the ketogenic diet are sometimes used to offset these side effects and reduce the non-compliance.

Some ketogenic variants

Ketogenic diet variants include modified Atkins diet, low glycemic index treatment, and medium chain diet. The ketogenic diet consists of 4:1 ratio of fat to carbohydrates shifting metabolism to the use of ketone bodies as a source of energy. A lower ratio is sometimes employed called the modified ketogenic diet with a 3:1 or 2:1 ratio of fat to carbohydrates. In the modified ketogenic diet, the palatability is improved and avoids the gastrointestinal symptoms associated with the ketogenic diet such as nausea. With the modified Atkins diet, carbohydrates are restricted to 10-20 grams a day, or a 1-2:1 ratio of protein to fat plus carbohydrates. In the low glycemic index treatment, carbohydrates are limited to 40-60 grams while 50-60% of the diet is fat and 20-30% is from protein. The medium-chain triglyceride diet employs oils as a supplement such as coconut oil. The palatability of these diets improve patient compliance and lessen the side effects of the ketogenic diet. Some patients also used the diets to incidentally lose weight in addition to treating seizures (2).

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Effectiveness of the ketogenic diet and ketogenic diet variants

One study summarizing studies on patients using the classic ketogenic diet found that 50% of patients out of 206 had a >50% reduction of seizures using the classic ketogenic diet. Older patients seemed to benefit less. In the modified Atkins diet, seizures were reduced in younger patients with more frequent seizures. Patients tended to drop out because of the side effects, lack of perceived effectiveness and because of the restrictions in the diet. Patients greater than 12 years old were less adherent to the diet (3).

It is possible that the protective effects of the ketogenic diet are related to the medium chain triglyceride fatty acids and not the ketone bodies.

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About

Introduction/Disclaimer

References

1. Augustin, et al, “Mechanism of action for medium-chain triglyceride ketogenic diet and metabolic disorders,” Lancet Neurology, 2018, Jan., 84-93.

2. McDonald, et al, “Ketogenic diets for adults with highly refractory epilepsy,” Epilepsy Currents, 2017, Nov.-Dec., 17(6):346-350.

3. Payne, et al, “The ketogenic and related diets in adolescents and adults-a review,” Epilepsia, 2011, Oct., 52(11):1941-1948.

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multiple sclerosis

Multiple sclerosis: stem cell therapy and its role in remyelination

Virginia Thornley, M.D., Neurologist

February 25, 2018

Stem cell research is a fast-growing arm of science. Multiple sclerosis is an autoimmune disease where the central nervous system is attacked as foreign. Clinical symptoms depend on the area involved, primarily in the white matter. Scientific research is being more and more directed towards agents and treatment modalities that differ from today’s immunomodulating agents given the potentially devastating side effects of the more efficacious medications. The heavy hitters tend to be more serious adverse effects.

How stem cell administration works

Umbilical cord mesenchymal stem cells may play a significant role in tissue repair and immunomodulatory processes that are important in multiple sclerosis. Stem cells divide into different types of cells which give rise to different tissues. They hold a wealth of potential in repairing damaged tissue as that found in multiple sclerosis. In one study, the mesenchymal stem cells from the umbilical cord were found with low immunogenicity. They can inhibit the multiplication of killer cells, T lymphocytes, and B lymphocytes and can inhibit the maturation of dendritic cells. Mesenchymal stem cells migrate to the site of injury and proliferate to repair damaged tissue.

Different stem cells that can be used in multiple sclerosis

Other types of stem cells are derived from hematopoeitic, embryonic, neural, spermatogonic, adipose, endometrial, Wharton jelly surrounding the umbilical cord and pluripotent-induced stem cells.

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Stem cell administration in 2 patients and reduction of abnormal MRI abnormalities

In one study, 2 patients were treated with stem cells. Clinical symptoms were reduced in the 1st patient, they were followed 8 years and found without adverse effects. The 2nd patient progressed and the timing of stem cell administration was shortened resulting in the reduction of symptoms. The number of abnormal foci seen in the MRI of the brain was less suggesting remyelination of damaged tissue within the brain. During illness, the body increases the immunogenicity with amplification of inhibitory co-stimulatory signals. With stem cell administration, this process reduces these destructive immune processes. Umbilical cord mesenchymal cells were found to inhibit IL-17c, HLA-DRB1, and IL-2 thereby protecting against an autoimmune response. The mechanism of action by which the stem cells work favors a remyelination repairing the damaged area(1).

Stem cell research in a study of 20 patients and reduction in disability

In another larger study of 20 patients, mesenchymal stem cell neural progenitor was applied. Results showed 70% had improved muscle strength and 50% improved in bladder symptoms. Improved EDSS (Expanded Disability Status Scale) was noted in 40% of patients, there were some minor adverse effects (2).

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Larger clinical randomized case control trials are needed.

 Introduction/Disclaimer
References
  1. Meng, et al, “Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis,” American Journal of Translational Research, 2018, 10(1): 212-223.
  2. Harris, et al, “Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis,” EBioMedicine, 2018, Feb., pii.S2352-3964 (18)30051-3 (Epub ahead of print)
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mold

Mold exposure: adverse effects of mycotoxins can still occur long after remote exposure

Virginia Thornley, M.D., General Neurologist, Epileptologist

February 23, 2018

Introduction

Water damaged buildings produce mold with airborne spores and hyphae floating as tiny particles in the air. The mycotoxins responsible for causing disease are called classified as aflatoxins, ochratoxin, and macrocyclic trichothecene. Even with remote exposure of up to decades, the ill effects from mold and mycotoxins can still be manifest.

10551440_10152611714523841_7526391710540820046_oWhy mold can still exert its effects even after many years of exposure

Mycotoxins are the toxins emitted by the mold that cause disease. These are detectable in the body of an affected individual in the urine, serum, breast milk, placenta, and even the umbilical cord. Some common molds that can be found are Aspergillus, Penicillium, Trichoderma, Stachybotrys chartarum. Some mold can be shed as fine airborne fragments. Nasal passages can harbor fine particulate mold which is not necessarily detected by spore counts. Nasal passages can harbor these fragments causing colonization for years.

Why treatment of mold exposure can be difficult

In one study, biofilm within the nasal passages was found to be present causing resistance to treatment. Biofilms occur when the microorganisms are embedded in the extracellular matrix.  The formation of a biofilm occurs by attachment to the cell membrane, multiplication of hyphae, packing and cross-linking on the cell channel and spore formation. There is some genetic involvement which may impart resistance to antifungal treatment or an up-regulation of metabolic pathways that were established by the hyphae.

In addition, there may be an interaction of bacteria with the mold in synergy. Bacteria that are sometimes found concomitant to the discovery of hyphae in the body include Staphylococcus aureus,  which is the most common. Hemophilus influenza incurs less severe disease. Staphylococcus aureus coagulase negative is also found in nasal passages.

The biofilm acts as a wall against antifungals making patients resistant to treatment.It leads to continuous colonization and proliferation of the fungus making treatment refractory(1)

10515259_10152611708578841_5684356889525088244_o.jpgNovel modalities in reducing fungal burden

First includes avoidance of further exposure to mycotoxins. It was found that in addition to being exposed to mold, affected individuals develop hypersensitivity to other chemicals after exposure. These include pesticides, organophosphates, bisphenol, benzophenone found in sunblock, perfluorocarbons found in non-stick coatings, heavy metals and solvents among others.

Why mycotoxins cause neurological disorders

Glutathione deficiency is found in those exposed to water damaged buildings. Glutathione deficiency causes cell degeneration and severe mitochondrial destruction. This deficiency may occur in the brain resulting in mitochondrial damage which may lead to neurological symptoms. Replacement may help. Oxidative stress-mediated impairment in the mitochondria is supported in animal models with aflatoxin. Neurotoxicity is also seen from oxidative stress mechanisms.

Vitamins and substances that can help with mycotoxin toxicity including Coenzyme Q10, Vitamin A, C, B, melatonin, Ginseng and whey protein

Additional anti-oxidants may be beneficial in neurotoxic injury including coenzyme Q10, vitamin D, magnesium, zinc and B deficiencies. In one animal study, cellular changes including DNA changes could be restored using whey protein and Korean ginseng. The whey protein supplies cysteine which is the rate-limiting step in glutathione creation. Licorice extract was found protective against destructive changes in an animal model where oflatoxin was introduced. Nitrosative tissue destruction caused by aflatoxin can be reduced with melatonin supplements in another animal study. Vitamins A, C, B was studied in the human model. When human lymphocytes were exposed to aflatoxin there was reduced GSH, and superoxide dismutase and glutathione peroxidase. Simultaneous use of Vitamins A, C, and B restored these levels to normal.

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  1. Brewer, et al, “Chronic illlness associated with mold and mycotoxins: is nasosinus biofilm the culprit?”  Toxins, 2014, Jan. 6(1)66-80.
  2. Thrasher, et al, “Water damaged home and health of occupants: a case study,” Journal of Environmental Health, 2012, 2012:312836.
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migraine

Magnesium: a natural alternative therapeutic agent for migraines

By Virginia Thornley, M.D., Neurologist

February 21, 2018

Many migraine sufferers are turning more towards all natural organic ways of managing migraines disillusioned by the side effects of conventional medications. Much attention is directed towards safe, healthy non-prescription agents in dealing with medical conditions. There is growing attention directed towards a more natural way of dealing with migraines with the incompletely effective measures that are available through conventional medicine. Several nutraceutical options are found to have growing evidence of effectiveness including magnesium, feverfew, coenzyme Q and riboflavin(1). Level B evidence exists for riboflavin, magnesium and feverfew(2). They have been found to be useful in treating the pediatric population because the risk of side effects is less(4). Many physicians practicing evidence-based medicine are still very reluctant to recommend nutraceuticals despite evidence in the literature of its effectiveness. This seeks to explore the mechanism of action and studies supporting the use of magnesium in migraine management.

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Proof is in the pudding

Doctors are reluctant to advise using supplements but there is a growing body of evidence supporting its use. In one report reviewing a wide range of studies evaluating the use of magnesium in migraine Level I evidence supports the use of magnesium in managing migraine(5). Magnesium is an important cofactor in many metabolic processes in the body. Optimizing its use appears well-documented in several medical conditions including migraine. In one study, there was a 50% reduction in the number of days with migraine using magnesium which increased in number of days the longer the supplement was used (6). With high dose IV magnesium in another study, in 93% of patients the migraine attack ended, in 1% the symptoms reduced in severity, in 100% the accompanying symptoms disappeared(7). High dose IV is a conventional treatment widely used in the hospital setting to abort debilitating migraines and often part of the “migraine cocktail” widely used in the ER setting.

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How does magnesium in a migraine work?

Magnesium is a mineral found naturally in the diet and is used in IV form to break the excruciating condition status migrainosus in the hospital setting. It is frequently used as a safe, healthy organic measure in migraine prevention. It has been found that people with migraines are magnesium deficient compared to healthy controls. Magnesium deficiency may be important in platelet hyperaggregation(3), cortical spreading depression, affect serotonin receptor function and affect many neurotransmitters and their release and functions. Migraineurs may suffer from magnesium deficiency due to genetic abnormalities, abnormal renal secretion and reduced consumption in the diet among other mechanisms. Magnesium may be deficient in more than 50% of patients warranting a trial in all migraine sufferers. It cannot be measured in the blood because most of the mineral is found in the bone at about 67% and intracellularly at 31% leaving less than 2% that can be measured extracellularly.

Consult with your neurologist.

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  1. D’Onofrio, et al, “Usefulness of nutraceuticals in migraine prophylaxis,” Neurological Science, 2017, May, 38 (Suppl1):117-120.
  2. Tepper, et al, “Nutraceutical and other modalities of treatment for migraine,”Continuum: Lifelong Learning, 2015, August, 21 (4, Headache);1018-31.
  3. Mauskop, et al, “Why all migraine patients should be treated with magnesium,”Journal Neural. Transm., 2012, May, 119(5):575-579.
  4. Sangermani, et al, “The use of nutraceuticals in children’s and adolescent’s migraines,”Neurological Science, 2017, May, 38 (Suppl 1):121-124.
  5. Schwalfenberg, et al, “The importance of magnesium in clinical healthcare,” Scientifica (Cairo), 2017:4179326.
  6. Guilbot, et al, “A combination of coenzymeQ10, feverfew and magnesium for migraine prophylaxis: a prospective observational study,” BMC Complement. Altern. Medicine, 2017, Aug., 30 (7):433.
  7. Demirkaya, et al, “Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks,”Headache, 2001, Feb., 41(2):171-7.
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