Neurodegenerative Diseases due to Neurotoxins passing through the Nose-to-Brain Pathway
Main Article Content
Abstract
Three neurodegenerative disorders- Alzheimer’s dementia (ALZ), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)- share a common feature in their pathogenesis: evidence of mitochondrial dysfunction and reactive oxygen stress. Their pathologic classifications are based on the findings at autopsy based on patterns of protein aggregates in neurons and glial cells. This pathology supports the concept that neurotoxins are a major factor in the etiology of these disorders. There is value in exploring the similarities in the pathogenesis of ALS, Parkinson Disease and Alzheimer Dementia based on non-genetic etiologies.
The nose to olfactory pathway feeds sensory input from the nasal cavity to the olfactory bulb and the entorhinal lobe. Another component of these pathways involves two branches of the trigeminal nerve with sensory input to the pons and midbrain. A key factor is their capacity to bypass the blood-brain barrier (BBB). The protection of the brain by the BBB diminishes with age and can be lost with damage from insults as with viral infections. The olfactory nerve is the only cranial nerve with direct exposure to the ambient environment and has a high rate of turnover of sensory receptors.
The nasal cavity is being studied for drug delivery and can be used to deliver medications into the central nervous system (CNS. The nose-to-brain pathway may represent a critical avenue of exposure to oxidative neurotoxins. Neurotoxic mycotoxins are a major risk to humans. Neurotoxins may be amplified by the nose-to-brain pathway. The pathology shows similarities to prion disease. These neurotoxins are highly fat-soluble and tend to accumulate in mitochondria and synaptic vesicles. Neurotoxins in synaptic vesicles can migrate from neuron to neuron.
There is evidence of chronic fungal infections in ALS patients that secret neurotoxic and immunotoxic mycotoxins leading to progressive immune suppression. The nose-to-olfactory pathway may amplify neurotoxins levels in the brain. If Parkinson Disease and ALZ are due to systemic poisonings, the source of neurotoxins may be episodic and lead to autoimmune disease.
Keywords:
Neurodegenerative, ALS, Parkinson's Disease, Alzheimer Dementia, Olfactory to Brain Pathway, Blood Brain Barrier, Immune Dysfunction, Immunotherapy
Article Details
How to Cite
REID, William Kirkpatrick.
Neurodegenerative Diseases due to Neurotoxins passing through the Nose-to-Brain Pathway.
Medical Research Archives, [S.l.], v. 11, n. 6, june 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3898>. Date accessed: 09 may 2024.
doi: https://doi.org/10.18103/mra.v11i6.3898.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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41. Alonso R, Pisa D, Fernandez-Fernandez AM, Rabano A, Carrasco L. Fungal infection in neural tissue of patients with amyotrophic lateral sclerosis. Neurobiol Dis. 2017;108:249-260.
42. Alonso R, Pisa D, Marina AI, et al. Evidence for fungal infection in cerebrospinal fluid and brain tissue from patients with amyotrophic lateral sclerosis. Int J Biol Sci. 2015;11(5):546-558.
43. Thornton CR. Detection of the 'Big Five' mold killers of humans: Aspergillus, Fusarium, Lomentospora, Scedosporium and Mucormycetes. Adv Appl Microbiol. 2020;110:1-61.
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48. Dai C, Xiao X, Sun F, et al. T-2 toxin neurotoxicity: role of oxidative stress and mitochondrial dysfunction. Arch Toxicol. 2019;93(11):3041-3056.
49. Weidner M, Lenczyk M, Schwerdt G, Gekle M, Humpf HU. Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture. Chem Res Toxicol. 2013;26(3):347-355.
50. Köck J, Gottschalk C, Ulrich S, Schwaiger K, Gareis M, Niessen L. Rapid and selective detection of macrocyclic trichothecene producing Stachybotrys chartarum strains by loop-mediated isothermal amplification (LAMP). Anal Bioanal Chem. 2021;413(19):4801-4813.
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58. Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med. 2019;45(10):1360-1371.
59. Chen X, Mu P, Zhu L, et al. T-2 Toxin Induces Oxidative Stress at Low Doses via Atf3ΔZip2a/2b-Mediated Ubiquitination and Degradation of Nrf2. Int J Mol Sci. 2021;22(15).
60. Zhang J, You L, Wu W, et al. The neurotoxicity of trichothecenes T-2 toxin and deoxynivalenol (DON): Current status and future perspectives. Food Chem Toxicol. 2020;145:111676.
61. Cistaro A, Valentini MC, Chiò A, et al. Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset. Eur J Nucl Med Mol Imaging. 2012;39(2):251-259.
62. Lyon MS, Wosiski-Kuhn M, Gillespie R, Caress J, Milligan C. Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology. Muscle Nerve. 2019;59(1):10-22.
63. Lastres-Becker I, Porras G, Arribas-Blázquez M, et al. Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy. Int J Mol Sci. 2021;22(6).
64. Nagy N. Establishment of EBV-Infected Lymphoblastoid Cell Lines. Methods Mol Biol. 2017;1532:57-64.
2. Jeromin A, Bowser R. Biomarkers in Neurodegenerative Diseases. Adv Neurobiol. 2017;15:491-528.
3. Chen H, Wang K, Scheperjans F, Killinger B. Environmental triggers of Parkinson's disease - Implications of the Braak and dual-hit hypotheses. Neurobiol Dis. 2022; 163:105601.
4. Horsager J, Knudsen K, Sommerauer M. Clinical and imaging evidence of brain-first and body-first Parkinson's disease. Neurobiol Dis. 2022;164:105626.
5. Prediger RD, Aguiar AS, Jr., Matheus FC, et al. Intranasal administration of neurotoxicants in animals: support for the olfactory vector hypothesis of Parkinson's disease. Neurotox Res. 2012;21(1):90-116.
6. Jeong SH, Jang JH, Lee YB. Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors. J Pharm Investig. 2022:1-34.
7. Hallschmid M. Intranasal insulin. J Neuroendocrinol. 2021;33(4):e12934.
8. Wang Z, Xiong G, Tsang WC, Schätzlein AG, Uchegbu IF. Nose-to-Brain Delivery. J Pharmacol Exp Ther. 2019;370(3):593-601.
9. Lochhead JJ, Wolak DJ, Pizzo ME, Thorne RG. Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration. J Cereb Blood Flow Metab. 2015;35(3):371-381.
10. Lochhead JJ, Davis TP. Perivascular and Perineural Pathways Involved in Brain Delivery and Distribution of Drugs after Intranasal Administration. Pharmaceutics. 2019;11(11).
11. Arce-López B, Alvarez-Erviti L, De Santis B, et al. Biomonitoring of Mycotoxins in Plasma of Patients with Alzheimer's and Parkinson's Disease. Toxins (Basel). 2021;13(7).
12. Dujardin S, Hyman BT. Tau Prion-Like Propagation: State of the Art and Current Challenges. Adv Exp Med Biol. 2019;1184:305-325.
13. Choi JS, Jang SS, Kim J, Hur K, Ference E, Wrobel B. Association Between Olfactory Dysfunction and Mortality in US Adults. JAMA Otolaryngol Head Neck Surg. 2021;147(1):49-55.
14. Pang NY, Song H, Tan BKJ, et al. Association of Olfactory Impairment With All-Cause Mortality: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2022;148(5):436-445.
15. Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8(1):7.
16. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959-1972.
17. Sassani M, Alix JJ, McDermott CJ, et al. Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis. Brain. 2020;143(12):3603-3618.
18. Pagani M, Chiò A, Valentini MC, et al. Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis. Neurology. 2014;83(12):1067-1074.
19. Verber NS, Shepheard SR, Sassani M, et al. Biomarkers in Motor Neuron Disease: A State of the Art Review. Front Neurol. 2019;10:291.
20. Lochhead JJ, Kellohen KL, Ronaldson PT, Davis TP. Distribution of insulin in trigeminal nerve and brain after intranasal administration. Sci Rep. 2019;9(1):2621.
21. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH, 2nd. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127(2):481-496.
22. Thorne RG, Hanson LR, Ross TM, Tung D, Frey WH, 2nd. Delivery of interferon-beta to the monkey nervous system following intranasal administration. Neuroscience. 2008;152(3):785-797.
23. Avgerinos KI, Kalaitzidis G, Malli A, Kalaitzoglou D, Myserlis PG, Lioutas VA. Intranasal insulin in Alzheimer's dementia or mild cognitive impairment: a systematic review. J Neurol. 2018;265(7):1497-1510.
24. Rickels MR, Ruedy KJ, Foster NC, et al. Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study. Diabetes Care. 2016;39(2):264-270.
25. Lasley SM. The Use of Intracerebral Microdialysis to Elucidate Environmentally Induced Neurotoxic Mechanisms. Curr Protoc Toxicol. 2019;80(1):e72.
26. Lin F, Luo SQ. Mitochondria in neurodegenerative diseases. CNS Neurosci Ther. 2019;25(7):813-815.
27. Ostermeyer-Shoaib B, Patten BM. IgG subclass deficiency in amyotrophic lateral sclerosis. Acta Neurol Scand. 1993;87(3):192-194.
28. Beers DR, Appel SH. Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies. Lancet Neurol. 2019;18(2):211-220.
29. Thonhoff JR, Simpson EP, Appel SH. Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis. Curr Opin Neurol. 2018;31(5):635-639.
30. Gustafson MP, Staff NP, Bornschlegl S, et al. Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis. PLoS One. 2017;12(7):e0182002.
31. Wu Q, Qin Z, Kuca K, et al. An update on T-2 toxin and its modified forms: metabolism, immunotoxicity mechanism, and human exposure assessment. Arch Toxicol. 2020; 94(11):3645-3669.
32. Patil NK, Bohannon JK, Sherwood ER. Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression. Pharmacol Res. 2016;111:688-702.
33. Patil NK, Guo Y, Luan L, Sherwood ER. Targeting Immune Cell Checkpoints during Sepsis. Int J Mol Sci. 2017;18(11).
34. Steinhagen F, Schmidt SV, Schewe JC, Peukert K, Klinman DM, Bode C. Immunotherapy in sepsis - brake or accelerate? Pharmacol Ther. 2020;208:107476.
35. Nakamori Y, Park EJ, Shimaoka M. Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway. Front Immunol. 2020;11:624279.
36. Lazdon E, Stolero N, Frenkel D. Microglia and Parkinson's disease: footprints to pathology. J Neural Transm (Vienna). 2020; 127(2):149-158.
37. De Virgilio A, Greco A, Fabbrini G, et al. Parkinson's disease: Autoimmunity and neuroinflammation. Autoimmun Rev. 2016; 15(10):1005-1011.
38. Leblhuber F, Ehrlich D, Steiner K, et al. The Immunopathogenesis of Alzheimer's Disease Is Related to the Composition of Gut Microbiota. Nutrients. 2021;13(2).
39. Muhammed M, Anagnostou T, Desalermos A, et al. Fusarium infection: report of 26 cases and review of 97 cases from the literature. Medicine (Baltimore). 2013; 92(6):305-316.
40. Reid WK. Mycotoxins causing amyotrophic lateral sclerosis. Med Hypotheses. 2021; 149:110541.
41. Alonso R, Pisa D, Fernandez-Fernandez AM, Rabano A, Carrasco L. Fungal infection in neural tissue of patients with amyotrophic lateral sclerosis. Neurobiol Dis. 2017;108:249-260.
42. Alonso R, Pisa D, Marina AI, et al. Evidence for fungal infection in cerebrospinal fluid and brain tissue from patients with amyotrophic lateral sclerosis. Int J Biol Sci. 2015;11(5):546-558.
43. Thornton CR. Detection of the 'Big Five' mold killers of humans: Aspergillus, Fusarium, Lomentospora, Scedosporium and Mucormycetes. Adv Appl Microbiol. 2020;110:1-61.
44. Salehi E, Hedayati MT, Zoll J, et al. Discrimination of Aspergillosis, Mucormycosis, Fusariosis, and Scedosporiosis in Formalin-Fixed Paraffin-Embedded Tissue Specimens by Use of Multiple Real-Time Quantitative PCR Assays. J Clin Microbiol. 2016; 54(11):2798-2803.
45. van Diepeningen AD, Brankovics B, Iltes J, van der Lee TA, Waalwijk C. Diagnosis of Fusarium Infections: Approaches to Identification by the Clinical Mycology Laboratory. Curr Fungal Infect Rep. 2015; 9(3):135-143.
46. Tortorano AM, Richardson M, Roilides E, et al. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clin Microbiol Infect. 2014;20 Suppl 3:27-46.
47. Alshannaq A, Yu JH. Occurrence, Toxicity, and Analysis of Major Mycotoxins in Food. Int J Environ Res Public Health. 2017;14(6).
48. Dai C, Xiao X, Sun F, et al. T-2 toxin neurotoxicity: role of oxidative stress and mitochondrial dysfunction. Arch Toxicol. 2019;93(11):3041-3056.
49. Weidner M, Lenczyk M, Schwerdt G, Gekle M, Humpf HU. Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture. Chem Res Toxicol. 2013;26(3):347-355.
50. Köck J, Gottschalk C, Ulrich S, Schwaiger K, Gareis M, Niessen L. Rapid and selective detection of macrocyclic trichothecene producing Stachybotrys chartarum strains by loop-mediated isothermal amplification (LAMP). Anal Bioanal Chem. 2021;413(19):4801-4813.
51. Burge PS. Sick building syndrome. Occup Environ Med. 2004;61(2):185-190.
52. Weidner M, Hüwel S, Ebert F, Schwerdtle T, Galla HJ, Humpf HU. Influence of T-2 and HT-2 toxin on the blood-brain barrier in vitro: new experimental hints for neurotoxic effects. PLoS One. 2013;8(3):e60484.
53. Thonhoff JR, Beers DR, Zhao W, et al. Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e465.
54. Grimaldi D, Pradier O, Hotchkiss RS, Vincent JL. Nivolumab plus interferon-γ in the treatment of intractable mucormycosis. Lancet Infect Dis. 2017;17(1):18.
55. Katragkou A, Roilides E. Immunotherapy of infections caused by rare filamentous fungi. Clin Microbiol Infect. 2012;18(2):134-139.
56. Delsing CE, Gresnigt MS, Leentjens J, et al. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect Dis. 2014;14:166.
57. Chang KC, Burnham CA, Compton SM, et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care. 2013;17(3):R85.
58. Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med. 2019;45(10):1360-1371.
59. Chen X, Mu P, Zhu L, et al. T-2 Toxin Induces Oxidative Stress at Low Doses via Atf3ΔZip2a/2b-Mediated Ubiquitination and Degradation of Nrf2. Int J Mol Sci. 2021;22(15).
60. Zhang J, You L, Wu W, et al. The neurotoxicity of trichothecenes T-2 toxin and deoxynivalenol (DON): Current status and future perspectives. Food Chem Toxicol. 2020;145:111676.
61. Cistaro A, Valentini MC, Chiò A, et al. Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset. Eur J Nucl Med Mol Imaging. 2012;39(2):251-259.
62. Lyon MS, Wosiski-Kuhn M, Gillespie R, Caress J, Milligan C. Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology. Muscle Nerve. 2019;59(1):10-22.
63. Lastres-Becker I, Porras G, Arribas-Blázquez M, et al. Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy. Int J Mol Sci. 2021;22(6).
64. Nagy N. Establishment of EBV-Infected Lymphoblastoid Cell Lines. Methods Mol Biol. 2017;1532:57-64.