endorphins/LDN

March 5, 2004

....based on the scientific data..some facts

1. Patients with any kind of MS have lower levels of beta-endorphins

than normals.

2. Patients with RRMS have more endorphins than the progressive

forms (normals have the most).

3. The levels of endorphins are less when the lesion is active

(gadolinium enhancing), as compared to non-active.

4. Interferon beta INCREASES beta endorphins

This suggests that endorphin deficiency is bad.. associated with

progression, active lesions etc.

Where LDN comes in is that it blocks some of the receptors in the

brain where beta-endorphins can bind and perhaps get degraded. This

means that the available endorphins will increase (because they are

being produced but not degraded). This presumably has beneficial

effects.

Hopefully this clears up some. The article detailing the endorphin

levels is below.

Yash

Journal of Neurology, Neurosurgery and Psychiatry, April 2003 v74 i4

p495(3)

[beta] endorphin concentrations in PBMC of patients with different

clinical phenotypes of multiple sclerosis. (Short Report). M.

Gironi; R. Furlan; M. Rovaris; G. Comi; M. Filippi; A.E. Panerai; P.

Sacerdote.

The possible link between the opioid peptide [bETA] endorphin and

the heterogeneity of the clinical course of multiple sclerosis (MS)

was investigated. Peripheral blood mononuclear cells (PBMC)

concentrations of [bETA] endorphin were measured in 50 patients in

different phases of MS. Thirty nine patients also underwent post-

contrast magnetic resonance imaging of the brain. Among MS forms,

the highest [bETA] endorphin concentrations were found in PBMC from

patients with relapsing remitting MS and the lowest in patients with

the progressive forms. Average [bETA] endorphin concentrations were

lower, although not significantly, in patients with than in those

without magnetic resonance imaging enhanced lesions. These data

suggest that [bETA] endorphin may have a role in the downregulation

of the inflammatory process.

**********

The immunological mechanisms of multiple sclerosis (MS) are only

partially defined, but they are known to differ between patients and

in different phases of the disease. (1) Several studies have shown a

pronounced increase of Th1 cytokines in patients with active

disease, (2) whereas interteukin 10, transforming growth factor

[bETA], and interleukin 4 have been found to be downregulated during

phases of disease activity and upregulated during phases of disease

remission. (3) Among non-conventional immune mediators, the opioid

peptide [bETA] endorphin has been shown to affect some immune

responses, which in turn modulate cytokine production. (4) [bETA]

Endorphin is synthesised by cells of the central nervous system

(arcuate nucleus) and immune system (lymphocytes, thymocytes,

monocytes, and splenocytes). (5) We have previously evaluated [bETA]

endorphin concentrations in peripheral blood mononuclear cells

(PBMC) of patients with MS. We found reduced concentrations of PBMC

[bETA] endorphin in patients compared with healthy controls,

increased concentrations of [bETA] endorphin during interferon beta

treatment compared with basal values, and increased concentrations

of [bETA] endorphin soon after a clinical relapse. (4) In this

study, we investigated the possible role of [bETA] endorphin in

determining the heterogeneity of the course of MS. To this end, we

measured [bETA] endorphin concentrations in PBMC from patients with

MS with clinically different phenotypes or in different phases of

the disease.

PATIENTS AND METHODS

Fifty patients with clinically definite MS (6) and 12 healthy

controls entered the study. We classified MS into relapsing

remitting, primary progressive, secondary progressive, benign, and

clinically relapsing, according to established clinical criteria (6)

(table I).

None of the patients had ever taken disease modifying treatments

(such as interferons, glatiramer acetate, mithoxantrone) or were

being treated with neuroleptic, antidepressant, or antiepileptic

drugs.

Patients experiencing relapses started steroid treatment after blood

sample collection

[bETA] Endorphin concentrations were also measured in 12 healthy

controls (five men and seven women) with a mean (SD) age of 40.0

(4.4) years.

In all patients and controls, peripheral blood samples were

collected in a tube containing EDTA, and PBMC were separated by

gradient sedimentation over Ficoll-Paque (Pharmacia, Uppsala,

Sweden). Aprotinin (Boehringer Ingeiheim Pharmaceutical Inc,

Ridgefield, Connecticut, USA) 1000 kIU was added to all samples

before storage at -20[degrees] to inhibit peptide degradation. Cells

were resuspended in 1 ml of 0.1 normal acetic acid, homogenised, and

centrifuged. Supernatants were frozen for radioimmunoassy. (4) The

antiserum and radiommunoassay procedures to measure [bETA] endorphin

were previously described and validated. (4) The antiserum used was

directed to the C terminal sequence of human [bETA] endorphin.

Sensitivity of the method was 10 pg per tube, and intra-assay and

interassay variation coefficients were 8% and 11 % respectively.

In 39 patients, dual echo spin-echo and post-contrast (intravenous

gadolinium-DTPA, 0.1 mmol/kg) T1 weighted spin-echo magnetic

resonance images of the brain were also obtained within 48 hours

after blood sample collection. Images were acquired with a 1.5 T

scanner, with full brain coverage (the scan geometry was 24

contiguous, axial, 5 mm thick slices with approximately 1 x 1 mm in-

plane pixel resolution). The presence and number of gadolinium

enhanced lesions were assessed by an experienced observer following

published guidelines. (7)

Differences in [beta] endorphin concentrations were analysed by

analysis of variance, followed by post hoc Bonferroni corrected t

test. Correlations were evaluated with the Pearson product moment

correlation.

RESULTS

[beta] Endorphin concentrations in PBMC samples obtained from all

five groups of MS patients were significantly lower than those found

in healthy controls (fig 1A).

PBMC [beta] endorphin concentrations in the different disease groups

are shown in fig 1 B.

The highest [beta] endorphin concentrations were found in PBMC from

patiens with relapsing remitting, benign, and clinically relapsing

forms of MS.

Patients with primary and secondary progressive MS had the lowest

[beta] endorphin concentrations that were significantly different

from those of healthy controls.

Average [beta] endorphin concentrations were 50.2 (35.6) and 62.5

(37.8) pg/10 (6) cells in patients with (n = 11) and those without

(n = 28) gadolinium enhanced lesions. This difference was not

significant.

No significant correlation was found between the concentrations of

[beta] endorphin and patients' age, disease duration, and severity

(as measured by the expanded disability status scale score).

DISCUSSION

The results of this study confirm our previous data (4) showing

reduced [beta] endorphin concentrations in the immune cells of

patients with MS compared with controls. This group of controls was

very well matched with the patients in terms of age and sex, and

their health condition was carefully checked to rule out any past or

ongoing disease. Moreover, the concentrations of PBMC [beta]

endorphin in the present group of controls was comparable with those

found in other groups of controls. (4)

As is the case for other autoimmune diseases, MS is supposed to

result from an imbalance between proinfiammatory and anti-

inflammatory factors. As in other autoimmune diseases (such as

rheumatoid arthritis and Crohn's disease), [beta] endorphin

concentrations are decreased in MS. (4)

The aim of this study was investigating a possible role of [beta]

endorphin in the mechanisms leading to different clinical

expressions of MS. So far, classifications of MS subtypes have been

based largely on clinical phenomenology, but there is growing

evidence that the subgroups of MS also differ with respect to

epidemiology, pathogenesis, genetics, neuropathology, and

neuroimaging. (1)

In our study, the lowest PBMC [beta] endorphin concentrations were

linked to the progressive forms of MS; that is, primary progressive

and secondary progressive forms. On the other hand, patients

with " benign " and relapsing remitting forms have the highest

concentrations.

It remains to be elucidated whether the [beta] endorphin decrement

should be considered a mere epiphenomenon of MS progression or

rather to be a factor contributing to it.

However, data obtained in experimental autoimmune encephalomyelitis,

an animal model of MS. showed a worsening of disease severity after

[beta] endorphin blockade achieved with an opioid antagonist, (8)

suggesting a potentially protective role for [beta] endorphin in the

pathogenetic mechanisms of MS.

In our previous study, we obtained other data leading to speculation

that [beta] endorphin has a protective role. We found an increase of

[beta] endorphin concentrations during interferon beta treatment.

These results suggest that the opioid can be involved in the

downregulation of the inflammatory process, present in MS.

A possible mechanism for this protective role of [beta] endorphin

may be an involvement in cytokine balance. [beta] Endorphin is known

to shift the Th1/Th2 balance towards Th2, (4 9) while the removal of

the opioid tone by the antagonist naloxone induces an increase of

Th1 cytokines such as interleukin 2 and interferon gamma and a

decrease of interleukin 4. (9)

Moreover, recent findings from our group suggest that the effects of

opioids on Th1/Th2 balance can be mediated by a decrease of the

production of interleukin 12 by macrophages. (10) This observation

may be particularly intriguing since macrophages and macrophage

cytokines are considered to be central factors involved in the onset

and progression of MS. 4 (11)

The observation that [beta] endorphin concentrations were, on

average, lower in patients with magnetic resonance imaging evidence

of ongoing MS activity also supports the concept that this compound

may have a role in downregulating MS inflammatory processes.

Clearly, we cannot completely rule out that mechanisms leading to MS

progression may influence [beta] endorphin concentrations. A

longitudinal study evaluating the modification of the peptide over

time would be helpful in elucidating this point. However, measuring

this opioid may be valuable in defining new characteristics of the

various clinical phenotypes of MS.

[FIGURE 1 OMITTED]

Table 1

Clinical and demographic characteristics of patients with multiple

sclerosis

Subgroup Number of patients Male/Female Age (years)

Relapsing remitting 17 6/11 35.7 (7.7)

Primary progressive 10 5/5 41.6 (10.7)

Secondary progressive 8 4/4 42.6 (7.1)

Benign 5 0/5 45.2 (6.6)

Clinically relapsing 10 3/7 37.2 (8.3)

Healthy controls 12 5/7 40.0 (4.4)

Subgroup EDSS score Disease duration (years)

Relapsing remitting 2.6 (1.5) 6.8 (6.8)

Primary progressive 4.1 (1.5) 8.5 (7.4)

Secondary progressive 4.1 (1.2) 10.6 (6.8)

Benign 2.3 (0.9) 19.8 (4.9)

Clinically relapsing 3.15 (2.0) 8.9 (6.0)

Healthy controls

Data are mean (SD). EDSS, expanded disability status scale.

Received 27 August 2002

In revised form 20 December 2002

Accepted 2 January 2003

REFERENCES

(1.) Lucchinetti CF, Bruck W, M, et al. Distinct pattern

of multiple sclerosis pathology indicates heterogeneity on

pathogenesis. Brain Pathol 1996;6:259-74.

(2.) Navikas V, He B, Link J, et al. Augmented expression of tumour

necrosis factor-alpha and lymphotoxin in mononuclear cells in

multiple sclerosis and optic neuritis. Brain 1996;119:213-23.

(3.) Clerici M, Saresella M, Trabattoni D, et a1. Single-cell

analysis of cytokine production show different immune profile in

multiple sclerosis patients with active or qui

escent disease, J

Neuroimmunol 2001;121:88-101.

(4.) Gironi M, elli V, Brambilla E, et al. Beta-endorphin

concentrations in peripheral blood mononuclear cells of patients

with multiple sclerosis. Arch Neural 2000;57:1178-81.

(5.) Blalock JE. A molecular basis for bidirectional communication

between the immune and neuroendocrine systems. Physiol Rev 1989;69:1-

32.

(6.) Mc WI, Compston A, Edan G, et al. Recommended diagnostic

criteria for multiple sclerosis: guidelines from the international

panel on the diagnosis of multiple sclerosis. Ann Neural 2001;50:121-

7.

(7.) Rovaris M, Barkhof F, Bostianello S, et al. Multiple sclerosis:

interobserver agreement in reporting active lesions on serial brain

MRI using conventional spin echo, fast spin echo, fast fluid-

attenuated inversion recovery and post-contrast Tl-weighted images.

J Neural 1999;246:920-5.

(8.) Panerai A, Radulovic J, Monastra G, et al. Beta-endorphin

concentrations in brain areas and peritoneal macrophages in rats

susceptible and resistant to experimental allergic

encephalomyelitis: a possible relationship between tumor necrosis

factor alpha and opioids in the disease. J Neural 1994;51:169-76.

(9.) Sacerdote P, Manfredi B, Gasponi L, et al. The opioid

antagonist naloxone induces a shift from type 2 to type 1 cytokine

pattern in BALB/cJ mice. Blood 2000;95:2031-6.

(10.) Sacerdote P, Limiroli E, Gospani L, et al. Modulation of

macrophage cytokine production by morphine and specific opioid

agonists [abstract]. Inflammation Res 2001;50(suppl 3):127.

(11.) Moser M, KM. Dendritic cell regulation of TH1-TH2

development. Nat Immunol 2000;1:199-205.

March 5, 2004

Dear Yash,

Thanks so much for that study! I have posted it to my EN Group

where we have members with Crohn's--I understand that the clinical

trial will be for Crohn's. We are turning the tide--word is getting

out. Anyone know a celebrity who has Crohn's? Nothing like competition

for a good story! Also does anyone have connections to local news

channels? Makes a great human interest and health story...Hey, I'm

just brainstorming here.

Love,

> ...based on the scientific data..some facts

> 1. Patients with any kind of MS have lower levels of beta-endorphins

> than normals.

> 2. Patients with RRMS have more endorphins than the progressive

> forms (normals have the most).

> 3. The levels of endorphins are less when the lesion is active

> (gadolinium enhancing), as compared to non-active.

> 4. Interferon beta INCREASES beta endorphins

>

> This suggests that endorphin deficiency is bad.. associated with

> progression, active lesions etc.

>

> Where LDN comes in is that it blocks some of the receptors in the

> brain where beta-endorphins can bind and perhaps get degraded. This

> means that the available endorphins will increase (because they are

> being produced but not degraded). This presumably has beneficial

> effects.

>

> Hopefully this clears up some. The article detailing the endorphin

> levels is below.

>

> Yash

>

> Journal of Neurology, Neurosurgery and Psychiatry, April 2003 v74 i4

> p495(3)

> [beta] endorphin concentrations in PBMC of patients with different

> clinical phenotypes of multiple sclerosis. (Short Report). M.

> Gironi; R. Furlan; M. Rovaris; G. Comi; M. Filippi; A.E. Panerai; P.

> Sacerdote.

>

> The possible link between the opioid peptide [bETA] endorphin and

> the heterogeneity of the clinical course of multiple sclerosis (MS)

> was investigated. Peripheral blood mononuclear cells (PBMC)

> concentrations of [bETA] endorphin were measured in 50 patients in

> different phases of MS. Thirty nine patients also underwent post-

> contrast magnetic resonance imaging of the brain. Among MS forms,

> the highest [bETA] endorphin concentrations were found in PBMC from

> patients with relapsing remitting MS and the lowest in patients with

> the progressive forms. Average [bETA] endorphin concentrations were

> lower, although not significantly, in patients with than in those

> without magnetic resonance imaging enhanced lesions. These data

> suggest that [bETA] endorphin may have a role in the downregulation

> of the inflammatory process.

>

> **********

>

> The immunological mechanisms of multiple sclerosis (MS) are only

> partially defined, but they are known to differ between patients and

> in different phases of the disease. (1) Several studies have shown a

> pronounced increase of Th1 cytokines in patients with active

> disease, (2) whereas interteukin 10, transforming growth factor

> [bETA], and interleukin 4 have been found to be downregulated during

> phases of disease activity and upregulated during phases of disease

> remission. (3) Among non-conventional immune mediators, the opioid

> peptide [bETA] endorphin has been shown to affect some immune

> responses, which in turn modulate cytokine production. (4) [bETA]

> Endorphin is synthesised by cells of the central nervous system

> (arcuate nucleus) and immune system (lymphocytes, thymocytes,

> monocytes, and splenocytes). (5) We have previously evaluated [bETA]

> endorphin concentrations in peripheral blood mononuclear cells

> (PBMC) of patients with MS. We found reduced concentrations of PBMC

> [bETA] endorphin in patients compared with healthy controls,

> increased concentrations of [bETA] endorphin during interferon beta

> treatment compared with basal values, and increased concentrations

> of [bETA] endorphin soon after a clinical relapse. (4) In this

> study, we investigated the possible role of [bETA] endorphin in

> determining the heterogeneity of the course of MS. To this end, we

> measured [bETA] endorphin concentrations in PBMC from patients with

> MS with clinically different phenotypes or in different phases of

> the disease.

>

> PATIENTS AND METHODS

>

> Fifty patients with clinically definite MS (6) and 12 healthy

> controls entered the study. We classified MS into relapsing

> remitting, primary progressive, secondary progressive, benign, and

> clinically relapsing, according to established clinical criteria (6)

> (table I).

>

> None of the patients had ever taken disease modifying treatments

> (such as interferons, glatiramer acetate, mithoxantrone) or were

> being treated with neuroleptic, antidepressant, or antiepileptic

> drugs.

>

> Patients experiencing relapses started steroid treatment after blood

> sample collection

>

> [bETA] Endorphin concentrations were also measured in 12 healthy

> controls (five men and seven women) with a mean (SD) age of 40.0

> (4.4) years.

>

> In all patients and controls, peripheral blood samples were

> collected in a tube containing EDTA, and PBMC were separated by

> gradient sedimentation over Ficoll-Paque (Pharmacia, Uppsala,

> Sweden). Aprotinin (Boehringer Ingeiheim Pharmaceutical Inc,

> Ridgefield, Connecticut, USA) 1000 kIU was added to all samples

> before storage at -20[degrees] to inhibit peptide degradation. Cells

> were resuspended in 1 ml of 0.1 normal acetic acid, homogenised, and

> centrifuged. Supernatants were frozen for radioimmunoassy. (4) The

> antiserum and radiommunoassay procedures to measure [bETA] endorphin

> were previously described and validated. (4) The antiserum used was

> directed to the C terminal sequence of human [bETA] endorphin.

>

> Sensitivity of the method was 10 pg per tube, and intra-assay and

> interassay variation coefficients were 8% and 11 % respectively.

>

> In 39 patients, dual echo spin-echo and post-contrast (intravenous

> gadolinium-DTPA, 0.1 mmol/kg) T1 weighted spin-echo magnetic

> resonance images of the brain were also obtained within 48 hours

> after blood sample collection. Images were acquired with a 1.5 T

> scanner, with full brain coverage (the scan geometry was 24

> contiguous, axial, 5 mm thick slices with approximately 1 x 1 mm in-

> plane pixel resolution). The presence and number of gadolinium

> enhanced lesions were assessed by an experienced observer following

> published guidelines. (7)

>

> Differences in [beta] endorphin concentrations were analysed by

> analysis of variance, followed by post hoc Bonferroni corrected t

> test. Correlations were evaluated with the Pearson product moment

> correlation.

>

> RESULTS

>

> [beta] Endorphin concentrations in PBMC samples obtained from all

> five groups of MS patients were significantly lower than those found

> in healthy controls (fig 1A).

>

> PBMC [beta] endorphin concentrations in the different disease groups

> are shown in fig 1 B.

>

> The highest [beta] endorphin concentrations were found in PBMC from

> patiens with relapsing remitting, benign, and clinically relapsing

> forms of MS.

>

> Patients with primary and secondary progressive MS had the lowest

> [beta] endorphin concentrations that were significantly different

> from those of healthy controls.

>

> Average [beta] endorphin concentrations were 50.2 (35.6) and 62.5

> (37.8) pg/10 (6) cells in patients with (n = 11) and those without

> (n = 28) gadolinium enhanced lesions. This difference was not

> significant.

>

> No significant correlation was found between the concentrations of

> [beta] endorphin and patients' age, disease duration, and severity

> (as measured by the expanded disability status scale score).

>

> DISCUSSION

>

> The results of this study confirm our previous data (4) showing

> reduced [beta] endorphin concentrations in the immune cells of

> patients with MS compared with controls. This group of controls was

> very well matched with the patients in terms of age and sex, and

> their health condition was carefully checked to rule out any past or

> ongoing disease. Moreover, the concentrations of PBMC [beta]

> endorphin in the present group of controls was comparable with those

> found in other groups of controls. (4)

>

> As is the case for other autoimmune diseases, MS is supposed to

> result from an imbalance between proinfiammatory and anti-

> inflammatory factors. As in other autoimmune diseases (such as

> rheumatoid arthritis and Crohn's disease), [beta] endorphin

> concentrations are decreased in MS. (4)

>

> The aim of this study was investigating a possible role of [beta]

> endorphin in the mechanisms leading to different clinical

> expressions of MS. So far, classifications of MS subtypes have been

> based largely on clinical phenomenology, but there is growing

> evidence that the subgroups of MS also differ with respect to

> epidemiology, pathogenesis, genetics, neuropathology, and

> neuroimaging. (1)

>

> In our study, the lowest PBMC [beta] endorphin concentrations were

> linked to the progressive forms of MS; that is, primary progressive

> and secondary progressive forms. On the other hand, patients

> with " benign " and relapsing remitting forms have the highest

> concentrations.

>

> It remains to be elucidated whether the [beta] endorphin decrement

> should be considered a mere epiphenomenon of MS progression or

> rather to be a factor contributing to it.

>

> However, data obtained in experimental autoimmune encephalomyelitis,

> an animal model of MS. showed a worsening of disease severity after

> [beta] endorphin blockade achieved with an opioid antagonist, (8)

> suggesting a potentially protective role for [beta] endorphin in the

> pathogenetic mechanisms of MS.

>

> In our previous study, we obtained other data leading to speculation

> that [beta] endorphin has a protective role. We found an increase of

> [beta] endorphin concentrations during interferon beta treatment.

> These results suggest that the opioid can be involved in the

> downregulation of the inflammatory process, present in MS.

>

> A possible mechanism for this protective role of [beta] endorphin

> may be an involvement in cytokine balance. [beta] Endorphin is known

> to shift the Th1/Th2 balance towards Th2, (4 9) while the removal of

> the opioid tone by the antagonist naloxone induces an increase of

> Th1 cytokines such as interleukin 2 and interferon gamma and a

> decrease of interleukin 4. (9)

>

> Moreover, recent findings from our group suggest that the effects of

> opioids on Th1/Th2 balance can be mediated by a decrease of the

> production of interleukin 12 by macrophages. (10) This observation

> may be particularly intriguing since macrophages and macrophage

> cytokines are considered to be central factors involved in the onset

> and progression of MS. 4 (11)

>

> The observation that [beta] endorphin concentrations were, on

> average, lower in patients with magnetic resonance imaging evidence

> of ongoing MS activity also supports the concept that this compound

> may have a role in downregulating MS inflammatory processes.

>

> Clearly, we cannot completely rule out that mechanisms leading to MS

> progression may influence [beta] endorphin concentrations. A

> longitudinal study evaluating the modification of the peptide over

> time would be helpful in elucidating this point. However, measuring

> this opioid may be valuable in defining new characteristics of the

> various clinical phenotypes of MS.

>

> [FIGURE 1 OMITTED]

>

> Table 1

>

> Clinical and demographic characteristics of patients with multiple

> sclerosis

>

> Subgroup Number of patients Male/Female Age (years)

>

> Relapsing remitting 17 6/11 35.7 (7.7)

> Primary progressive 10 5/5 41.6 (10.7)

> Secondary progressive 8 4/4 42.6 (7.1)

> Benign 5 0/5 45.2 (6.6)

> Clinically relapsing 10 3/7 37.2 (8.3)

> Healthy controls 12 5/7 40.0 (4.4)

>

> Subgroup EDSS score Disease duration (years)

>

> Relapsing remitting 2.6 (1.5) 6.8 (6.8)

> Primary progressive 4.1 (1.5) 8.5 (7.4)

> Secondary progressive 4.1 (1.2) 10.6 (6.8)

> Benign 2.3 (0.9) 19.8 (4.9)

> Clinically relapsing 3.15 (2.0) 8.9 (6.0)

> Healthy controls

>

> Data are mean (SD). EDSS, expanded disability status scale.

> Received 27 August 2002

>

> In revised form 20 December 2002

>

> Accepted 2 January 2003

>

> REFERENCES

>

> (1.) Lucchinetti CF, Bruck W, M, et al. Distinct pattern

> of multiple sclerosis pathology indicates heterogeneity on

> pathogenesis. Brain Pathol 1996;6:259-74.

>

> (2.) Navikas V, He B, Link J, et al. Augmented expression of tumour

> necrosis factor-alpha and lymphotoxin in mononuclear cells in

> multiple sclerosis and optic neuritis. Brain 1996;119:213-23.

>

> (3.) Clerici M, Saresella M, Trabattoni D, et a1. Single-cell

> analysis of cytokine production show different immune profile in

> multiple sclerosis patients with active or qui

> escent disease, J

> Neuroimmunol 2001;121:88-101.

>

> (4.) Gironi M, elli V, Brambilla E, et al. Beta-endorphin

> concentrations in peripheral blood mononuclear cells of patients

> with multiple sclerosis. Arch Neural 2000;57:1178-81.

>

> (5.) Blalock JE. A molecular basis for bidirectional communication

> between the immune and neuroendocrine systems. Physiol Rev 1989;69:1-

> 32.

>

> (6.) Mc WI, Compston A, Edan G, et al. Recommended diagnostic

> criteria for multiple sclerosis: guidelines from the international

> panel on the diagnosis of multiple sclerosis. Ann Neural 2001;50:121-

> 7.

>

> (7.) Rovaris M, Barkhof F, Bostianello S, et al. Multiple sclerosis:

> interobserver agreement in reporting active lesions on serial brain

> MRI using conventional spin echo, fast spin echo, fast fluid-

> attenuated inversion recovery and post-contrast Tl-weighted images.

> J Neural 1999;246:920-5.

>

> (8.) Panerai A, Radulovic J, Monastra G, et al. Beta-endorphin

> concentrations in brain areas and peritoneal macrophages in rats

> susceptible and resistant to experimental allergic

> encephalomyelitis: a possible relationship between tumor necrosis

> factor alpha and opioids in the disease. J Neural 1994;51:169-76.

>

> (9.) Sacerdote P, Manfredi B, Gasponi L, et al. The opioid

> antagonist naloxone induces a shift from type 2 to type 1 cytokine

> pattern in BALB/cJ mice. Blood 2000;95:2031-6.

>

> (10.) Sacerdote P, Limiroli E, Gospani L, et al. Modulation of

> macrophage cytokine production by morphine and specific opioid

> agonists [abstract]. Inflammation Res 2001;50(suppl 3):127.

>

> (11.) Moser M, KM. Dendritic cell regulation of TH1-TH2

> development. Nat Immunol 2000;1:199-205.

March 5, 2004

I have been in contact with Dr.Gironi in Italy re: her study. She

was not aware of the use of LDN for MS!. An excerpt of our

conversation is below. I will update her..lets see if this goes any

further. The important thing is to get the word out. A trial in

Europe is a possibility, fortunately big Pharma carries less clout

there.

Yash

<Thanks a lot for your precious informations.

I didn't know anything about the use of naltrexone (LDN) in MS

patients. I'm

really very interesting about that, would you mind to send me any

papers or

references reporting these miraculous results?

Are you working in neuroimmunology?

It should me nice to think about a pilot study, together......

Thanks again

Looking forward to hear from you

Myra>

> ...based on the scientific data..some facts

> 1. Patients with any kind of MS have lower levels of beta-

endorphins

> than normals.

> 2. Patients with RRMS have more endorphins than the progressive

> forms (normals have the most).

> 3. The levels of endorphins are less when the lesion is active

> (gadolinium enhancing), as compared to non-active.

> 4. Interferon beta INCREASES beta endorphins

>

> This suggests that endorphin deficiency is bad.. associated with

> progression, active lesions etc.

>

> Where LDN comes in is that it blocks some of the receptors in the

> brain where beta-endorphins can bind and perhaps get degraded. This

> means that the available endorphins will increase (because they are

> being produced but not degraded). This presumably has beneficial

> effects.

>

> Hopefully this clears up some. The article detailing the endorphin

> levels is below.

>

> Yash

>

> Journal of Neurology, Neurosurgery and Psychiatry, April 2003 v74

i4

> p495(3)

> [beta] endorphin concentrations in PBMC of patients with different

> clinical phenotypes of multiple sclerosis. (Short Report). M.

> Gironi; R. Furlan; M. Rovaris; G. Comi; M. Filippi; A.E. Panerai;

P.

> Sacerdote.

>

> The possible link between the opioid peptide [bETA] endorphin and

> the heterogeneity of the clinical course of multiple sclerosis (MS)

> was investigated. Peripheral blood mononuclear cells (PBMC)

> concentrations of [bETA] endorphin were measured in 50 patients in

> different phases of MS. Thirty nine patients also underwent post-

> contrast magnetic resonance imaging of the brain. Among MS forms,

> the highest [bETA] endorphin concentrations were found in PBMC from

> patients with relapsing remitting MS and the lowest in patients

with

> the progressive forms. Average [bETA] endorphin concentrations were

> lower, although not significantly, in patients with than in those

> without magnetic resonance imaging enhanced lesions. These data

> suggest that [bETA] endorphin may have a role in the downregulation

> of the inflammatory process.

>

> **********

>

> The immunological mechanisms of multiple sclerosis (MS) are only

> partially defined, but they are known to differ between patients

and

> in different phases of the disease. (1) Several studies have shown

a

> pronounced increase of Th1 cytokines in patients with active

> disease, (2) whereas interteukin 10, transforming growth factor

> [bETA], and interleukin 4 have been found to be downregulated

during

> phases of disease activity and upregulated during phases of disease

> remission. (3) Among non-conventional immune mediators, the opioid

> peptide [bETA] endorphin has been shown to affect some immune

> responses, which in turn modulate cytokine production. (4) [bETA]

> Endorphin is synthesised by cells of the central nervous system

> (arcuate nucleus) and immune system (lymphocytes, thymocytes,

> monocytes, and splenocytes). (5) We have previously evaluated

[bETA]