Additional uses of VIP

Additional uses of VIP

Dementia: intervene early before cognitive disability occurs

One clinical use of VIP follows early diagnosis of dementia. Neuronal loss is rarely sudden; the time from detection of gray matter nuclear atrophy to when overt dementia begins can be long. VIP dosing at 300-600mcg/day, taken over 6-9 months has been shown to be safe and effective. We have shown (unpublished) that the mechanism of VIP correction of early dementia usually stems from correction of the unregulated over-expression of coagulation genes using VIP provides clinical benefit seen in a small, but ever-growing number of patients. In younger-aged Alzheimer’s patients, improvement coincides with correction of coagulation genes, which in turn reduces overproduction of coagulation gene products.

We have known for years that CIRS patients will have the prothrombotic abnormalities in transcriptomics, first published in ciguatera (1), and seen in RNA Seq (2). Thanks in large part to the published work of a number of researchers, especially those from Rockefeller University (notably Sidney Strickland’s lab; 3, 4, 5, 6, 7, 8, 9 ,10, 11, 12, 13), the strength of the vascular hypothesis of Alzheimer’s makes additional clinical sense in CIRS patients. All those patients we saw with unexplained elevations of d-dimer, PAI-1 and von Willebrand’s factors, not to mention those Lyme patients with clotted PICC lines and CFS patients with pulmonary emboli, were telling us that a systemic coagulation problem was ongoing. Involvement of the brain ends up being no surprise, but only now we have a literature that tells us our observations on inflammation, cytokines and coagulation are supported.

The vascular hypothesis of neuronal injury and Alzheimer’s (AD) has evolved from observations in 2010 (7) that beta amyloid (AB) bound to fibrinogen, enhances thrombosis and reduces fibrinolysis in the CNS, and (possibly) contributes to neuronal loss.  Prior research (cited in 7) confirmed that AB bound to other mediators of inflammation and coagulation creates a prothrombotic state affecting CNS structures like the hippocampus, but also promotes systemic inflammation. Sounds like CIRS! Noting AD increases after systemic infection, Strickland, et al state in (7), “Activation and/or modulation of the delicately balanced coagulation and inflammatory systems by AB could lead… to chronic and pathological occlusion and inflammation, both of which could contribute to the neuronal death observed in AD.”

Data supports this idea, including AB interaction with fibrinogen, thereby leading to deposition of fibrin in cerebral blood vessels, inducing microinfarcts (and cerebral microbleeds) and loosening of the blood brain barrier. Since AB also activates Factor XII and XIII, the propensity for fibrin deposition is increased through the intrinsic coagulation system, inhibiting plasmin-fibrin interaction and by activating bradykinin.

Additional data, from biopsy specimens, as well as involving AB with Factor V, Factor XIII and integrins, demonstrates the role of AB binding to products of coagulation genes was related to cognitive deficits. Further, hypoxia promoted tau hyperphosphorylation (3). Tauopathies are a group of dementias that have in common the formation of intracellular filamentous deposits seeded by the microtubule-associated protein tau, in abnormally hyperphosphorylated form(s). Tau inclusions are common among all of these tauopathies leading to diverse phenotypic manifestations, brain dysfunction, and degeneration.

The coagulation problems are not just prothrombotic: risk of hypo-coagulation and bleeding after exposure to WDB is also shown by coagulation gene suppression.  In one isolated trial, correction of excessive abundance of actinomycetes by a room sanitizing device (iAdaptAir; Mold Congress, Fort Lauderdale, Florida, 1/2019), as the only therapy, reversed coagulation gene suppression and stopped intractable epistaxis. In a study in a single practice (RS) looking at von Willebrand’s profile in CIRS patients, over 1300 results showed that 66% of patients had abnormal findings, with 60% being predisposed to clotting and 40% to bleeding. Control patients had less than 5% each predisposed to clotting and bleeding. VIP protects us from over-and under-activity of coagulation genes.

References:                                                      

1. Transcriptomic signatures in whole blood ofpatients who acquire a chronic inflammatoryresponse syndrome (CIRS) following an exposureto the marine toxin ciguatoxin. Ryan J, Wu Q, Shoemaker R. BMC Medical Genomics (2015) 8:15.
2. Ryan, J, Shoemaker R. RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal polypeptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing. Medical Research Archives. 2016; 4(7): 1-11.
3. Raz L, Bhaskar K, Weaver J, Marini S, Zhang Q, Thompson J, Espinoza C, lqbal S, Maphis N, Weston L, Sillerud L, Caprihan A, Pesko J, Erhardt E, Rosenberg G. Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. Neurobiol Dis 2019; 126: 124-136.
4. Yang J, Lyu Y, Ma Y, Chen Y. Relationship between cerebral microbleeds location and cognitive impairment in patients with ischemic cerebrovascular disease. Neuroreport 2018; 29: 1209-1213.
5. Zamolodchikov D, Strickland S. A possible new role for AB in vascular and inflammatory dysfunction in Alzheimer’s disease. Thromb Res 2016; Suppl 2: S58-61.
6. Ahn H, Chen Z, Zamolodchikov D, Norris E, Strickland S. Interactions of B-amyloid peptide with fibrinogen and coagulation factor XII may contribute to Alzheimer’s disease. Curr Opin Hematol 2017; 24: 427-431.
7. Cortes-Cantell M. Paul J, Norris E, Bronstein R, Ahn H, Zamolodchikov D, Bhuvanendran S, Fenz K, Strickland S. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer’s disease.  Neuron 2010; 66: 695-709.
8. Canteli M, Zamolodchikov D, Ahn H, Strickland S, Norris E. Fibrinogen and altered hemostasis in Alzheimer’s disease. J Alzheimer Dis 2012 32: 599-608.
9. Page M, Thomson G, Nunes J, Engelbrecht A, Nell T, de Villiers W, de Beer M, Engelbrecht L, Kell D, Pretorius E. Serum amyloid A binds to fibrin (ogen), promoting fibrin amyloid formation. Sci Rep 2019; 9: 3102.
10. Hur W, Mazinani N, Lu X, Yefet L, Byrnes J, Ho L, Yeon J, Filipenko S, Wolberg A, Jefferies W, Kastrup C. Coagulation factor Xllla cross-links amyloid B into dimers and oligomers and to blood proteins. J Biol Chem 2019; 294: 390-396.
11. Suidan G, Singh P, Patel-Hett S, Lin Z, Volfson D, Yamamoto-Imoto H, Norris E, Bell R, Strickland S. Abnormal clotting of the intrinsic/contact pathway in Alzheimer’s disease patients is related to cognitive ability. Blood Advances 2018; 9: 954-963.
12. Luca C, Virtuoso A, Maggio N, Papa M. Neuro-coagulopathy: Blood coagulation factors in central nervous system disease. Molecular Science 2017; 18:
13. Chapman J. Coagulation in inflammatory diseases of the central nervous system. Semin Throm Hemost 2013; 39: 876-80

Correction of gray matter nuclear atrophy

In a paper published in 2017 (Shoemaker R, Katz D, McMahon S, Ryan J. Intranasal VIP safely restores atrophic grey matter nuclei in patients with CIRS. Internal Medicine Review 2017; 3(4): 1-14), Shoemaker and Ryan showed that VIP, taken intranasally at a daily dose of 600 mcg/day, safely reduced excessive gray matter nuclear atrophy in cases to equal controls. In unpublished practice experience since 2017, the salutary benefit has continued, with the additional benefit of correction of enlargement of superior lateral ventricles as well. While there are data that support correction of coagulation gene upregulation obtained retrospectively, not all patients follow this pattern. We are left to speculate regarding a physiologic mechanism induced by VIP, with restoration of Purkinje fiber contact is one such possibility.

Correction of CIRS caused by exposure to the interior environment of water-damaged buildings.

There is no better illumination of benefit from use of VIP than in the massive cohort of CIRS-WDB cases. We have data on hundreds of patients treated by VIP as the 12^th step of a treatment protocol. The VIP treatment summary has already been submitted in public commentary to the FDA.

Metabolic disturbances underlie abnormal metabolism in right ventricle and pulmonary vasculature in pulmonary hypertension

A large literature is developing in pulmonary hypertension (PAH) suggesting that in PAH, cellular shifts away from electron transport system generation of ATP to glucose oxidation adds to the physiologic disturbance in a subset of PAH patients. This metabolic shift parallels that seen in molecular hypometabolism seen in over 85% of patients with SEID, CIRS and chronic fatiguing illness in general. These metabolic disturbances can be shown to be based on suppression of ribosomal gene mRNA, possibly due to ribotoxins or ribosomal inactivating proteins that disrupt normal function of the sarcin-ricin loop.

References:

1. Petkov V, Burian B, Block L. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003; 111: 1339-1346.
2. Archer S, Fang Y, Ryan J, Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulmonary Circulation 2013; 3: 144-152.
3. Ryan J, Rich J, Maron B. Building the case for novel clinical trials in pulmonary arterial hypertension. Cir Cardiovasc Qual Outcomes 2015; 8: 114-123.
4. Ryan J, Archer S. Emerging concepts in the molecular basis of pulmonary arterial hypertension (PAH): Part 1: Metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in PAH. Circulation 2015; 131: 1691-1702.
5. Ryan J, Dasgupta A, Huston J, Chen K, Archer S. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med (Berl) 2015; 93: 229-242.
6. Sutendra G, Michelakis E. The metabolic basis of pulmonary arterial hypertension. Cell Metab 2014; 19: 558-73.
7. Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F, Fuchs B, Weisel F, Hecker M, Schermuly R, Grimminger F, Ghofrani H, Seeger W, Weissmann N. Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model. Am J Respir Cell Mol Biol 2013; 49: 358-67.
8. Dromparis P, Paulin R, Sutendra G, Qi A, Bonnet S, Michelakis E. Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res 2013; 113: 126-36.
9. McMurtry M, Bonnet S, Wu X, Dyck J, Haromy A, Hashimoto K, Michelakis E. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004; 95: 830-40.
10. Paulin R, Michelakis E. The metabolic theory of pulmonary arterial hypertension. Circ Res 2014; 115: 146-64.
11. Dromparis P, Sutendra G, Michelakis E. The role of mitochondria in pulmonary vascular remodeling. J Mol Med (Berl) 2010; 88: 1003-10.
12. Tuder R, Davis L, Graham B. Targeting energetic metabolism. A new frontier in the pathogenesis and treatment of pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 2012; 185: 260-266

Metabolic abnormalities in T cells, especially T regs and T effector cells, contribute to defective T cell function

What began as a simple observation of reduced numbers of acquired T reg cells (CD4+C25++) and thymus-derived T reg cells (CD4+CD25++CD 127 -/lo) in CIRS patients that was corrected by VIP has led to use of VIP in correction of molecular hypometabolism in CIRS patients. This in turn has led to a deeper understanding of accentuation of gamma interferon activated inhibition of translation (GAIT) as regulatory mechanism that prevents ongoing production of pyruvate in cells with molecular hypometabolism.

References:

1. Stienstra R, Netea-Maier N, Riksen N, Joosten L, Netea M. Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune response. Cell Metabolism 2017; 26: 142-156.
2. Arneth B. Activation of CD4 and CD8 T cell receptors and regulatory T cells in response to human proteins. Peer J 2018; 6: e4462.
3. Novello F, Gumaa A, McLean P. The pentose phosphate pathway of glucose metabolism. Biochem J 1969: 111: 713-725.
4. Chang C, Curtis J, Maggi L, Faubert B, Villarino A, Sullivan D, Huang S, vander Windt G, Blagih J, Qiu J, Weber J, Pearce E, Jones R, Pearce E. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153: 1239-1251.
5. Dimeloe S, Mehling M, Frick C, Loeliger J, Bantug G, Sauder U, Fischer M, Belle R, Develioglu L, Tay S, Langenkamp A, Hess C. The immune-metabolic basis of effector memory CD4 + T cell function under hypoxic conditions. J Immunol 2016; 196: 106-114.
6. Arif A, Chatterjee P, Moodt R, Fox P. Heterotrimeric GAIT complex drives transcript-selective translation inhibition in murine macrophages. Molecular and Cellular Biology 2012; 32: 5046-5055.