- Email: [email protected]
Endocrine and phototransduction effects in the prevention of multiple sclerosis
Medical Hypotheses 77 (2011) 1011–1014
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Endocrine and phototransduction effects in the prevention of multiple sclerosis James Moynihan a,⇑, Helena Moore b,1 a b
Killinane, Kanturk, Co. Cork, Ireland Bons Secours Hospital, Strand Street, Tralee, Co. Kerry, Ireland
a r t i c l e
i n f o
Article history: Received 12 May 2011 Accepted 17 August 2011
a b s t r a c t In addressing the question of what seems to prevent multiple sclerosis (MS) in the tropics this paper reviews work done by various researchers and suggests that MS incidence may be affected in the ensemble by the endocrine system’s response to environment temperature, the skin’s response to sunlight, and by the retina’s response to brightness. It shows how the hypouricemia which is a reliable indicator in MS patients can leave the blood–brain barrier unsealed in general but allow retinoids to block their access to the central nervous system. It presents published studies as evidence and suggests a number of straightforward tests of these theories which could allow clinicians to advise their MS patients to take appropriate actions to help slow down or prevent disease progression. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction One of the traditionally best known characteristics of MS is the latitudinal gradient of its incidence rate. The disease is almost unheard of in the tropics and its incidence rises with positive or negative latitude. In northern Europe it occurs in approximately 0.1% of the population. The reasons for this variation are probably various. Possible preventive mechanisms Normal reduction of uric acid excretion MS patients in relapse tend to have low plasma concentrations of uric acid. This issue has been addressed by Moore et al. [1]. In order to retain extra-cellular fluid in warm environments Na+ reabsorption at renal proximal tubules is increased by the renin-angiotensin-aldosterone system’s (RAAS) control loop. Via co-transport this should allow increased reabsorption of uric acid anions at the proximal tubules of the nephron and reduce the excretion of uric acid. Conversely, in cool situations where vasodilation is controlled neurologically to a greater extent, there is seldom a shortage of extra-cellular fluid and urate excretion is rarely restricted. This is, of course, largely a good thing since the main task of the kidneys is to excrete waste. But for the maintenance of a normal or high plasma uric acid concentration the opposite is required. A high or normal uric acid level may play a part in regulating the immune system’s access to brain tissue. Kean et al. [2] have shown this to be true in EAE experiments. ⇑ Corresponding author. Tel.: +353 29 78090. 1
E-mail address: [email protected] (J. Moynihan). Tel.: +353 66 714 9873.
0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.08.037
Also, warm environments cause the body to sweat for heat dissipation. Huang et al. [3] find that almost no uric acid is lost in sweat. They suggest that ‘‘Persons who take vigorous exercise or one exposed to hot environments would be well advised to drink adequate fluids since heavy sweating excretes only minimal uric acid and may diminish urinary excretions of uric acid.’’ Their focus is on maintaining low serum uric acid levels but their conclusion is completely consistent with the theory presented here. This selective barrier to uric acid at the end of the sweating process should have the effect of increasing, or at least maintaining, a normal plasma uric acid concentration while sweating occurs. People who avoid hot environments are likely to sweat less and will not benefit from any such plasma uric acid concentration boost caused by sweating. Various experiments show that the process of acclimatization to heat increases the body’s ability and tendency to sweat. For example, Henane and Valatx [4] that ‘‘Seven of the nine subjects in this study exhibited the phenomena classically observed during heat acclimatization of an early onset of sweating and a rapid increase in sweat rate.’’ This acclimatization process is consistent with the fact that people who grow up in the tropics are extremely unlikely to ever develop MS. Soluble (as opposed to crystalline) uric acid is reported in [5] to have an anti-inflammatory effect. And, as mentioned above, uric acid is reported in [2] to have the effect of sealing the blood–brain barrier in EAE experiments. HPA activity level and aldosterone concentration in the kidney There is a secondary effect associated with increased RAAS bias. Gaillard et al. [6] report that, ‘‘Angiotensin II and vasopressin were both able to potentiate the corticotropin releasing activity of CRF41.’’ This is an adaptive control effect. In an environment where
1012
J. Moynihan, H. Moore / Medical Hypotheses 77 (2011) 1011–1014
the bias levels of angiotensin and vasopressin are low the body needs a lower volume of steroids so the gain of the hypothalamus–pituitary–adrenal gland (HPA) axis is reduced. CRF varies the output of ACTH which affects the production of both aldosterone and cortisone. The anti-inflammatory effects of steroids are well known. And aldosterone modulates the kidney’s reabsorption of Na+ and is produced in the adrenal glands so even if normal steroid levels are maintained any variation in demand for aldosterone is likely to have an exaggerated effect on kidney-local aldosterone concentration and various renal reabsorption processes. So, even if steroid levels are properly regulated and are unchanged by environmental conditions, in a warmer environment there is a higher usage of aldosterone so the time-averaged levels of aldosterone at or near the source of the aldosterone should be higher. Vitamin D This issue has been well addressed by the scientific community. For example, Ramagopalan et al. [7] have shown that vitamin D interferes with various processes that are related to genes linked to MS susceptibility. The theories presented here are not inconsistent with any theories that pinpoint low vitamin D levels as playing a part in MS. Heat acclimatization and childhood uric acid levels Experiments show that acclimatization to heat lowers the temperature at which the body begins to sweat. The resultant greater demand for Na+ which enables an accompanying increased proximal tubule reabsorption of anions like uric acid may explain the fact that people who live in the tropics for the first fifteen years never go on to develop MS. It is likely that people who are acclimatized to heat as children are less likely to exhibit hypouricemia during their adolescent years and that this helps to, in effect, seal off the blood brain barrier more completely as the brain matures. It will also make it less likely that the person develops hypouricemia later in life since these people will always be more likely to stay warm. Takasi Igarashi [8] measures plasma uric acid levels in children at different ages. The data he provides in his brief paper is plotted in Fig. 1. In light of the brain-sealing effect of uric acid reported by Kean et al., the different uric acid levels for males and females may be responsible for the fact that MS is twice as common in females as it is in males. Phototransduction effects Sunlight intensity correlates very reliably with latitude. In fact, logic would dictate that if environmental temperature and sunlight intensity do in fact have a preventive effect then the high light
Pediatric plasma uric acid concentration
400
MicroMol/L
375
Male
350 325 300
Female
275 250 225 200
7
9
11
13
15
17
Age (years) Fig. 1. A plot of Takasi Igarishi’s pediatric plasma uric acid concentration data.
intensity factor on its own may be a sufficient condition for the prevention of MS. If the high temperature factor were a necessary condition then pockets of MS incidence would show up in cool areas near the equator. They do not. Huang et al. in [9] show that following recent demyelination, the genetics of retinoid receptors become expressed. In reporting on their experiments they claim that ‘‘RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture.’’ and find that the, ‘‘Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons.’’ They conclude, ‘‘Our results indicate that RXR-g is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.’’ This experimental investigation, of course, suggests a pharmacological treatment possibly involving the ingestion or infusion of retinoic acid in order to encourage oligodendrocyte formation. In another investigation of the effects of retinoids Royal et al. [10] plot a measure of cerebrospinal fluid (CSF) retinol content against plasma retinol concentration for a number of MS patients and a number of patients with other illnesses. The logical expectation for this plot should be some degree of proportionality or positive correlation since one would expect a transfer from one fluid to the other. But they measure a very strong negative correlation between the two concentration indicators in MS patients. This counter-intuitive negative correlation probably indicates that the retinoids are acting as blood–brain barrier blockers and as their concentration rises they block their own access to the CSF. (Both uric acid and sphingosine-1-phosphate are known to strengthen the blood–brain barrier. Both of these molecules feature carbonyl groups, so retinal, the aldehyde, is likely to be the brain blocking agent among the retinoids.) So in order to encourage remylination, an increased CNS retinoic acid concentration with its oligodendrocyte-developing ligand effect should be beneficial, but we have an indication that the retinoids themselves, probably including retinal, block their own access route from blood to CSF and brain tissue. (In fact, since retinoic acid acts as a signal for the formation of oligodendrocytes, the retinoids’ self-blocking mechanism is probably essential to prevent a spurious generation of oligodendrocytes and myelin whenever plasma levels of retinoids increase.) As mentioned above, data presented by Royal et al., seem to show that MS patients’ blood–brain barriers seem to block the passage of retinoids. Werner et al. have performed experiments and report in [11] that retinoic acid is formed from retinol in the adult rat brain. Phototransduction Another simple delivery route for the retinoids may exist. The retina itself, as the name suggests, produces retinoic acid. In the loop of reactions and transformations which constitute the chemistry of phototransduction in the retina the process of converting 11-cis-retinal to rhodopsin is slow and this lethargy is probably retained by evolution to allow a broad slow adaptation to various levels of brightness. We can draw an analogy. If water tumbles over a cliff at a fixed rate the amount of water churning at the base of the fall will vary in opposition to the scale of any process that removes water at the base. Thus, as various levels of brightness convert a limited stream of rhodopsin to metarhodopsin, the concentration of available rhodopsin should drop in bright light, thus providing a first simple layer of adaptation to brightness levels which can vary over many orders of magnitude. A side effect consequence of this scheme is that in bright conditions when the phototransduction loop is fully active there should
J. Moynihan, H. Moore / Medical Hypotheses 77 (2011) 1011–1014
be a larger backlog of retinal waiting for its conversion, (with scotopsin), back to rhodopsin. This dynamic ripple of retinal can either get reduced reversibly to retinol or irreversibly oxidized to retinoic acid. So it is likely that the retina’s production of retinoic acid should increase in bright conditions. McCaffery et al. [12] measure increased levels of retinoic acid in the retinae of mice after exposure to light. This could imply that, at least to some extent, levels of retinoic acid in brain tissue, blood and possibly the cerebro-spinal fluid should be increased by bright light, or dazzling situations and could be used to encourage remylination. As mentioned above, Huang et al. have shown the effects of ligand signaling retinoic acid on the maturation of oligodendrocytes. Previously to this, Massacesi et al. [13,14] have demonstrated an anti-inflammatory effect of retinoic acid in animals with experimental autoimmune encephalomyelitis (EAE). And Xu et al. [15] show that retinoic acid can ‘‘control EAE at least in part, by suppressing the production of NO and specific inflammatory cytokines from activated glia and suggests that RA might be effective in the treatment of MS.’’ In a study of identical twins Islam et al. [16] report that childhood exposure to bright sunlight seems to prevent MS. They suspect that the preventive mechanism is related to vitamin D. The analysis presented here suggests that sunlight exposure may provide a more regular production of retinoic acid in the central nervous system thereby encouraging a fuller supply of oligodendrocytes and possibly even simultaneously sealing the blood–brain barrier. Discussion This work focuses on two major environmental conditions: one is exposure to elevated temperature with its associated acclimatization, increased HPA gain and normal uric acid levels. The other is bright light which we suggest may cause increased generation of retinoic acid in the retina with an associated increased generation of oligodendrocytes. In the work by Royal et al. mentioned above, there is a curious, strong negative correlation between plasma retinol levels and a measure of CSF retinol levels in MS patients only. This retinoid sealing effect probably doesn’t show up in the non-MS data because the barrier is already sealed by uric acid itself. A unified theory of prevention Since carbonyl groups are reactive with protons when they are available, the bias of equilibrium of any retinol-retinal exchange reaction should be skewed far away from the aldehyde side when there is a healthy plasma uric acid concentration. This effect unifies the two halves of the work presented here. A normally high plasma concentration of uric acid should help to seal off the blood–brain barrier in general. And secondly, in a low pH environment aldehydes get reduced to alcohols so if retinal with its carbonyl group is responsible for blocking the blood–brain barrier in the Royal et al. plots, people with hypouricemia may have two problems: 1. a badly sealed blood–brain barrier in general so antibodies can attack the brain more easily, and 2. a blocked supply of retinoids to the brain. And we know from various papers that retinoic acid is a signal for oligodendrocyte differentiation. In fact the non-MS patient plot of CSF retinol metric versus plasma retinol concentration in the Royal et al. paper does show some signs of negative correlation at high plasma retinol concentration end of the graph. This would indicate that even in the presence
1013
of normal uric acid levels the retinoids block their own access to the CSF at high concentration levels. In fact, thinking logically about this, since we know that retinoic acid acts as a signal for oligodendrocyte differentiation in the brain, the retinoids’ path from plasma to CSF has to be regulated to some extent to prevent a spurious generation of oligodendrocytes and myelin when plasma levels fluctuate. So a high or normal plasma uric acid level should convert retinal to retinol, possibly preventing the blood–brain blocking action plotted by Royal et al. If retinal is the species of retinoid that blocks the blood brain barrier in the Royal plot, then hypouricemia may be blamed for failing to help block the blood–brain barrier in general and also for allowing the retinal to block the retinoids’ own supply route from plasma to brain. This may be crucial during childhood, especially in an environment where the retinae themselves aren’t producing large amounts of retinoic acid. Testing this theory All of this may justify some experiments, for example, 1. If acclimatization to heat is effective in preventing MS then a sample of MS patients in a country where saunas are common should have a significantly lower fraction of people who used saunas regularly during childhood and adolescence than a similar sample of the general population in the same country would have. 2. To find if bright light exposure could be effective, an animal study could determine to what extent retinoic acid levels in plasma, cerebrospinal fluid or brain tissue can be boosted by dazzling. 3. Since the cost of such experiments should be minimal, another set of tests could try to vary the progression rate of MS patients subjected to heat acclimatization, a dazzling routine, or both. 4. A part of the heat hypothesis described above is based on the idea that in warm environments autonomic nervous system vasoconstriction is reduced for normal circulation to the peripherals. The resulting increase in RAAS bias which should occur to compensate for this vasodilation could be imposed pharmacologically by the use of alpha blockers. These medications should interfere with the autonomic nervous system control of vasoconstriction and force the RAAS bias up in the same way. 5. Dazzling in combination with blood brain barrier-blocking medications such as Tysabri or Gilenya could be a particularly interesting candidate for investigation in MS treatment since, in theory, myelin loss should be curtailed and the retinoic acid treatment’s new myelin should have more of a positive effect. A note on disease progression and incidence Ironically, almost as soon as MS patients notice the symptoms of demyelination they tend to avoid both of the hypothetical disease preventing natural mechanisms discussed here, that is, heat and bright sunlight. They do this because they notice that when they get overheated, for example, by sunlight beating down on the back of the neck, their MS symptoms worsen immediately. And clinicians, of course, in order to prevent falls or other accidents, have to advise their MS patients against getting overheated. Then, of course, the more CNS lesions MS patients accumulate the more they notice their sensitivity to heat and the less they expose themselves to heat and bright sunlight. This is a behavioral positive feedback effect. It may be at least partly responsible for making the MS syndrome progress over time like a typical infectious disease.
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The prevention of progression The results of tests like these could allow clinicians to advise MS patients to take measures that would help avoid the behavioral positive feedback effect in the disease’s typical progression pattern. Of course ambulatory MS patients need to avoid overheating while walking but acclimatization to heat seems to be affected more by peak environment temperature than it does by average temperatures. Therefore patients could safely use electric blankets to acclimatize themselves and possibly avoid the hypouricemia which appears to be an integral part of the disease process. A dazzling regime could vary the retinoic acid levels. Of course these techniques would have to be tested before clinicians could advise MS patients to move to the tropics or buy electric blankets and spot lamps. Conflict of interest No author of this work has any conflict of interest. References [1] Moore H, Moynihan J. Endocrine system dynamics and MS epidemiology. Med Hypotheses 2010;74(5):814–7. [2] Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC. The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. J Immunol 2000;165:6511–8. [3] Huang CT, Chen ML, Huang LL, Mao IF. Uric acid and urea in human sweat. Chin J Physiol 2002;45(3):109–15.
[4] Henane R, Valatx JL. Thermoregulatory changes induced during heat acclimatization by controlled hyperthermia in man. J Physiol 1973;230(2):255–71. [5] Zare F, Magnusson M, Bergström T, Brisslert M, Josefsson E, Karlsson A, et al. Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis. J Leukoc Biol 2006;79:482–8. [6] Gaillard RC, Riondel AM, Ling N, Muller AF. Corticotropin releasing factor activity of CRF 41 in normal man is potentiated by angiotensin II and vasopressin but not by desmopressin. Life Sci 1988;43(23):1935–44. [7] Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1⁄1501 is regulated by vitamin D. 2009. Published on line at PLoS Genetics: www.plosgenetics.org. [8] Takashi Igarashi. Pediatric plasma uric acid levels. Pediatr Nephrol 1993. [9] Huang Jeffrey K, Jarjour Andrew A, Oumesmar Brahim Nait, Kerninon Christophe, Williams Anna, Kreze Wojciech, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 2010. [10] Royal W, Gartner S, Gajewski CD. Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis. Mult Scler 2002;8:452. [11] Werner Elizabeth A, Deluca Hector F. Retinoic acid is detected at relatively high levels in the CNS of adult rats. Am J Physiol Endocrinol Metab 2002;282:E672–8. [12] McCaffery Peter, Mey Jorg, Drager Ursula C. Light-mediated retinoic acid production. Proc Natl Acad Sci USA 1996;93:12570–4 [Neurobiol]. [13] Massacesi L, Abbamondi AL, Sarlo F, Amaducci L. The control of experimental allergic encephalomyelitis with retinoic acid. Further studies. Riv Neurol 1987;57:166–9. [14] Massacesi L, Castigli E, Vergelli M, Olivotto J, Abbamondi AL, Sarlo F, et al. Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats. J Clin Investig 1991;88:1331–7 [PubMed: 1918383]. [15] Xu Jihong, Drew Paul D. 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. Neuroimmunology 2006. [16] Islam Talat, James Gauderman W, Cozen Wendy, Mack Thomas M. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Endocrine and phototransduction effects in the prevention of multiple sclerosis James Moynihan a,⇑, Helena Moore b,1 a b
Killinane, Kanturk, Co. Cork, Ireland Bons Secours Hospital, Strand Street, Tralee, Co. Kerry, Ireland
a r t i c l e
i n f o
Article history: Received 12 May 2011 Accepted 17 August 2011
a b s t r a c t In addressing the question of what seems to prevent multiple sclerosis (MS) in the tropics this paper reviews work done by various researchers and suggests that MS incidence may be affected in the ensemble by the endocrine system’s response to environment temperature, the skin’s response to sunlight, and by the retina’s response to brightness. It shows how the hypouricemia which is a reliable indicator in MS patients can leave the blood–brain barrier unsealed in general but allow retinoids to block their access to the central nervous system. It presents published studies as evidence and suggests a number of straightforward tests of these theories which could allow clinicians to advise their MS patients to take appropriate actions to help slow down or prevent disease progression. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction One of the traditionally best known characteristics of MS is the latitudinal gradient of its incidence rate. The disease is almost unheard of in the tropics and its incidence rises with positive or negative latitude. In northern Europe it occurs in approximately 0.1% of the population. The reasons for this variation are probably various. Possible preventive mechanisms Normal reduction of uric acid excretion MS patients in relapse tend to have low plasma concentrations of uric acid. This issue has been addressed by Moore et al. [1]. In order to retain extra-cellular fluid in warm environments Na+ reabsorption at renal proximal tubules is increased by the renin-angiotensin-aldosterone system’s (RAAS) control loop. Via co-transport this should allow increased reabsorption of uric acid anions at the proximal tubules of the nephron and reduce the excretion of uric acid. Conversely, in cool situations where vasodilation is controlled neurologically to a greater extent, there is seldom a shortage of extra-cellular fluid and urate excretion is rarely restricted. This is, of course, largely a good thing since the main task of the kidneys is to excrete waste. But for the maintenance of a normal or high plasma uric acid concentration the opposite is required. A high or normal uric acid level may play a part in regulating the immune system’s access to brain tissue. Kean et al. [2] have shown this to be true in EAE experiments. ⇑ Corresponding author. Tel.: +353 29 78090. 1
E-mail address: [email protected] (J. Moynihan). Tel.: +353 66 714 9873.
0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.08.037
Also, warm environments cause the body to sweat for heat dissipation. Huang et al. [3] find that almost no uric acid is lost in sweat. They suggest that ‘‘Persons who take vigorous exercise or one exposed to hot environments would be well advised to drink adequate fluids since heavy sweating excretes only minimal uric acid and may diminish urinary excretions of uric acid.’’ Their focus is on maintaining low serum uric acid levels but their conclusion is completely consistent with the theory presented here. This selective barrier to uric acid at the end of the sweating process should have the effect of increasing, or at least maintaining, a normal plasma uric acid concentration while sweating occurs. People who avoid hot environments are likely to sweat less and will not benefit from any such plasma uric acid concentration boost caused by sweating. Various experiments show that the process of acclimatization to heat increases the body’s ability and tendency to sweat. For example, Henane and Valatx [4] that ‘‘Seven of the nine subjects in this study exhibited the phenomena classically observed during heat acclimatization of an early onset of sweating and a rapid increase in sweat rate.’’ This acclimatization process is consistent with the fact that people who grow up in the tropics are extremely unlikely to ever develop MS. Soluble (as opposed to crystalline) uric acid is reported in [5] to have an anti-inflammatory effect. And, as mentioned above, uric acid is reported in [2] to have the effect of sealing the blood–brain barrier in EAE experiments. HPA activity level and aldosterone concentration in the kidney There is a secondary effect associated with increased RAAS bias. Gaillard et al. [6] report that, ‘‘Angiotensin II and vasopressin were both able to potentiate the corticotropin releasing activity of CRF41.’’ This is an adaptive control effect. In an environment where
1012
J. Moynihan, H. Moore / Medical Hypotheses 77 (2011) 1011–1014
the bias levels of angiotensin and vasopressin are low the body needs a lower volume of steroids so the gain of the hypothalamus–pituitary–adrenal gland (HPA) axis is reduced. CRF varies the output of ACTH which affects the production of both aldosterone and cortisone. The anti-inflammatory effects of steroids are well known. And aldosterone modulates the kidney’s reabsorption of Na+ and is produced in the adrenal glands so even if normal steroid levels are maintained any variation in demand for aldosterone is likely to have an exaggerated effect on kidney-local aldosterone concentration and various renal reabsorption processes. So, even if steroid levels are properly regulated and are unchanged by environmental conditions, in a warmer environment there is a higher usage of aldosterone so the time-averaged levels of aldosterone at or near the source of the aldosterone should be higher. Vitamin D This issue has been well addressed by the scientific community. For example, Ramagopalan et al. [7] have shown that vitamin D interferes with various processes that are related to genes linked to MS susceptibility. The theories presented here are not inconsistent with any theories that pinpoint low vitamin D levels as playing a part in MS. Heat acclimatization and childhood uric acid levels Experiments show that acclimatization to heat lowers the temperature at which the body begins to sweat. The resultant greater demand for Na+ which enables an accompanying increased proximal tubule reabsorption of anions like uric acid may explain the fact that people who live in the tropics for the first fifteen years never go on to develop MS. It is likely that people who are acclimatized to heat as children are less likely to exhibit hypouricemia during their adolescent years and that this helps to, in effect, seal off the blood brain barrier more completely as the brain matures. It will also make it less likely that the person develops hypouricemia later in life since these people will always be more likely to stay warm. Takasi Igarashi [8] measures plasma uric acid levels in children at different ages. The data he provides in his brief paper is plotted in Fig. 1. In light of the brain-sealing effect of uric acid reported by Kean et al., the different uric acid levels for males and females may be responsible for the fact that MS is twice as common in females as it is in males. Phototransduction effects Sunlight intensity correlates very reliably with latitude. In fact, logic would dictate that if environmental temperature and sunlight intensity do in fact have a preventive effect then the high light
Pediatric plasma uric acid concentration
400
MicroMol/L
375
Male
350 325 300
Female
275 250 225 200
7
9
11
13
15
17
Age (years) Fig. 1. A plot of Takasi Igarishi’s pediatric plasma uric acid concentration data.
intensity factor on its own may be a sufficient condition for the prevention of MS. If the high temperature factor were a necessary condition then pockets of MS incidence would show up in cool areas near the equator. They do not. Huang et al. in [9] show that following recent demyelination, the genetics of retinoid receptors become expressed. In reporting on their experiments they claim that ‘‘RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture.’’ and find that the, ‘‘Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons.’’ They conclude, ‘‘Our results indicate that RXR-g is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.’’ This experimental investigation, of course, suggests a pharmacological treatment possibly involving the ingestion or infusion of retinoic acid in order to encourage oligodendrocyte formation. In another investigation of the effects of retinoids Royal et al. [10] plot a measure of cerebrospinal fluid (CSF) retinol content against plasma retinol concentration for a number of MS patients and a number of patients with other illnesses. The logical expectation for this plot should be some degree of proportionality or positive correlation since one would expect a transfer from one fluid to the other. But they measure a very strong negative correlation between the two concentration indicators in MS patients. This counter-intuitive negative correlation probably indicates that the retinoids are acting as blood–brain barrier blockers and as their concentration rises they block their own access to the CSF. (Both uric acid and sphingosine-1-phosphate are known to strengthen the blood–brain barrier. Both of these molecules feature carbonyl groups, so retinal, the aldehyde, is likely to be the brain blocking agent among the retinoids.) So in order to encourage remylination, an increased CNS retinoic acid concentration with its oligodendrocyte-developing ligand effect should be beneficial, but we have an indication that the retinoids themselves, probably including retinal, block their own access route from blood to CSF and brain tissue. (In fact, since retinoic acid acts as a signal for the formation of oligodendrocytes, the retinoids’ self-blocking mechanism is probably essential to prevent a spurious generation of oligodendrocytes and myelin whenever plasma levels of retinoids increase.) As mentioned above, data presented by Royal et al., seem to show that MS patients’ blood–brain barriers seem to block the passage of retinoids. Werner et al. have performed experiments and report in [11] that retinoic acid is formed from retinol in the adult rat brain. Phototransduction Another simple delivery route for the retinoids may exist. The retina itself, as the name suggests, produces retinoic acid. In the loop of reactions and transformations which constitute the chemistry of phototransduction in the retina the process of converting 11-cis-retinal to rhodopsin is slow and this lethargy is probably retained by evolution to allow a broad slow adaptation to various levels of brightness. We can draw an analogy. If water tumbles over a cliff at a fixed rate the amount of water churning at the base of the fall will vary in opposition to the scale of any process that removes water at the base. Thus, as various levels of brightness convert a limited stream of rhodopsin to metarhodopsin, the concentration of available rhodopsin should drop in bright light, thus providing a first simple layer of adaptation to brightness levels which can vary over many orders of magnitude. A side effect consequence of this scheme is that in bright conditions when the phototransduction loop is fully active there should
J. Moynihan, H. Moore / Medical Hypotheses 77 (2011) 1011–1014
be a larger backlog of retinal waiting for its conversion, (with scotopsin), back to rhodopsin. This dynamic ripple of retinal can either get reduced reversibly to retinol or irreversibly oxidized to retinoic acid. So it is likely that the retina’s production of retinoic acid should increase in bright conditions. McCaffery et al. [12] measure increased levels of retinoic acid in the retinae of mice after exposure to light. This could imply that, at least to some extent, levels of retinoic acid in brain tissue, blood and possibly the cerebro-spinal fluid should be increased by bright light, or dazzling situations and could be used to encourage remylination. As mentioned above, Huang et al. have shown the effects of ligand signaling retinoic acid on the maturation of oligodendrocytes. Previously to this, Massacesi et al. [13,14] have demonstrated an anti-inflammatory effect of retinoic acid in animals with experimental autoimmune encephalomyelitis (EAE). And Xu et al. [15] show that retinoic acid can ‘‘control EAE at least in part, by suppressing the production of NO and specific inflammatory cytokines from activated glia and suggests that RA might be effective in the treatment of MS.’’ In a study of identical twins Islam et al. [16] report that childhood exposure to bright sunlight seems to prevent MS. They suspect that the preventive mechanism is related to vitamin D. The analysis presented here suggests that sunlight exposure may provide a more regular production of retinoic acid in the central nervous system thereby encouraging a fuller supply of oligodendrocytes and possibly even simultaneously sealing the blood–brain barrier. Discussion This work focuses on two major environmental conditions: one is exposure to elevated temperature with its associated acclimatization, increased HPA gain and normal uric acid levels. The other is bright light which we suggest may cause increased generation of retinoic acid in the retina with an associated increased generation of oligodendrocytes. In the work by Royal et al. mentioned above, there is a curious, strong negative correlation between plasma retinol levels and a measure of CSF retinol levels in MS patients only. This retinoid sealing effect probably doesn’t show up in the non-MS data because the barrier is already sealed by uric acid itself. A unified theory of prevention Since carbonyl groups are reactive with protons when they are available, the bias of equilibrium of any retinol-retinal exchange reaction should be skewed far away from the aldehyde side when there is a healthy plasma uric acid concentration. This effect unifies the two halves of the work presented here. A normally high plasma concentration of uric acid should help to seal off the blood–brain barrier in general. And secondly, in a low pH environment aldehydes get reduced to alcohols so if retinal with its carbonyl group is responsible for blocking the blood–brain barrier in the Royal et al. plots, people with hypouricemia may have two problems: 1. a badly sealed blood–brain barrier in general so antibodies can attack the brain more easily, and 2. a blocked supply of retinoids to the brain. And we know from various papers that retinoic acid is a signal for oligodendrocyte differentiation. In fact the non-MS patient plot of CSF retinol metric versus plasma retinol concentration in the Royal et al. paper does show some signs of negative correlation at high plasma retinol concentration end of the graph. This would indicate that even in the presence
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of normal uric acid levels the retinoids block their own access to the CSF at high concentration levels. In fact, thinking logically about this, since we know that retinoic acid acts as a signal for oligodendrocyte differentiation in the brain, the retinoids’ path from plasma to CSF has to be regulated to some extent to prevent a spurious generation of oligodendrocytes and myelin when plasma levels fluctuate. So a high or normal plasma uric acid level should convert retinal to retinol, possibly preventing the blood–brain blocking action plotted by Royal et al. If retinal is the species of retinoid that blocks the blood brain barrier in the Royal plot, then hypouricemia may be blamed for failing to help block the blood–brain barrier in general and also for allowing the retinal to block the retinoids’ own supply route from plasma to brain. This may be crucial during childhood, especially in an environment where the retinae themselves aren’t producing large amounts of retinoic acid. Testing this theory All of this may justify some experiments, for example, 1. If acclimatization to heat is effective in preventing MS then a sample of MS patients in a country where saunas are common should have a significantly lower fraction of people who used saunas regularly during childhood and adolescence than a similar sample of the general population in the same country would have. 2. To find if bright light exposure could be effective, an animal study could determine to what extent retinoic acid levels in plasma, cerebrospinal fluid or brain tissue can be boosted by dazzling. 3. Since the cost of such experiments should be minimal, another set of tests could try to vary the progression rate of MS patients subjected to heat acclimatization, a dazzling routine, or both. 4. A part of the heat hypothesis described above is based on the idea that in warm environments autonomic nervous system vasoconstriction is reduced for normal circulation to the peripherals. The resulting increase in RAAS bias which should occur to compensate for this vasodilation could be imposed pharmacologically by the use of alpha blockers. These medications should interfere with the autonomic nervous system control of vasoconstriction and force the RAAS bias up in the same way. 5. Dazzling in combination with blood brain barrier-blocking medications such as Tysabri or Gilenya could be a particularly interesting candidate for investigation in MS treatment since, in theory, myelin loss should be curtailed and the retinoic acid treatment’s new myelin should have more of a positive effect. A note on disease progression and incidence Ironically, almost as soon as MS patients notice the symptoms of demyelination they tend to avoid both of the hypothetical disease preventing natural mechanisms discussed here, that is, heat and bright sunlight. They do this because they notice that when they get overheated, for example, by sunlight beating down on the back of the neck, their MS symptoms worsen immediately. And clinicians, of course, in order to prevent falls or other accidents, have to advise their MS patients against getting overheated. Then, of course, the more CNS lesions MS patients accumulate the more they notice their sensitivity to heat and the less they expose themselves to heat and bright sunlight. This is a behavioral positive feedback effect. It may be at least partly responsible for making the MS syndrome progress over time like a typical infectious disease.
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The prevention of progression The results of tests like these could allow clinicians to advise MS patients to take measures that would help avoid the behavioral positive feedback effect in the disease’s typical progression pattern. Of course ambulatory MS patients need to avoid overheating while walking but acclimatization to heat seems to be affected more by peak environment temperature than it does by average temperatures. Therefore patients could safely use electric blankets to acclimatize themselves and possibly avoid the hypouricemia which appears to be an integral part of the disease process. A dazzling regime could vary the retinoic acid levels. Of course these techniques would have to be tested before clinicians could advise MS patients to move to the tropics or buy electric blankets and spot lamps. Conflict of interest No author of this work has any conflict of interest. References [1] Moore H, Moynihan J. Endocrine system dynamics and MS epidemiology. Med Hypotheses 2010;74(5):814–7. [2] Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC. The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. J Immunol 2000;165:6511–8. [3] Huang CT, Chen ML, Huang LL, Mao IF. Uric acid and urea in human sweat. Chin J Physiol 2002;45(3):109–15.
[4] Henane R, Valatx JL. Thermoregulatory changes induced during heat acclimatization by controlled hyperthermia in man. J Physiol 1973;230(2):255–71. [5] Zare F, Magnusson M, Bergström T, Brisslert M, Josefsson E, Karlsson A, et al. Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis. J Leukoc Biol 2006;79:482–8. [6] Gaillard RC, Riondel AM, Ling N, Muller AF. Corticotropin releasing factor activity of CRF 41 in normal man is potentiated by angiotensin II and vasopressin but not by desmopressin. Life Sci 1988;43(23):1935–44. [7] Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1⁄1501 is regulated by vitamin D. 2009. Published on line at PLoS Genetics: www.plosgenetics.org. [8] Takashi Igarashi. Pediatric plasma uric acid levels. Pediatr Nephrol 1993. [9] Huang Jeffrey K, Jarjour Andrew A, Oumesmar Brahim Nait, Kerninon Christophe, Williams Anna, Kreze Wojciech, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 2010. [10] Royal W, Gartner S, Gajewski CD. Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis. Mult Scler 2002;8:452. [11] Werner Elizabeth A, Deluca Hector F. Retinoic acid is detected at relatively high levels in the CNS of adult rats. Am J Physiol Endocrinol Metab 2002;282:E672–8. [12] McCaffery Peter, Mey Jorg, Drager Ursula C. Light-mediated retinoic acid production. Proc Natl Acad Sci USA 1996;93:12570–4 [Neurobiol]. [13] Massacesi L, Abbamondi AL, Sarlo F, Amaducci L. The control of experimental allergic encephalomyelitis with retinoic acid. Further studies. Riv Neurol 1987;57:166–9. [14] Massacesi L, Castigli E, Vergelli M, Olivotto J, Abbamondi AL, Sarlo F, et al. Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats. J Clin Investig 1991;88:1331–7 [PubMed: 1918383]. [15] Xu Jihong, Drew Paul D. 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. Neuroimmunology 2006. [16] Islam Talat, James Gauderman W, Cozen Wendy, Mack Thomas M. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007.