Dehydroepiandrosterone DHEA in the
of Lipopolysaccharide-induced Parkinsonism (a Case Report)
A 22-year old laboratory worker developed a Parkinson’s syndrome, with bradykinesia, rigidity, tremor, and cogwheel phenomenon, three weeks after an acute poisoning with 10 microgram Salmonella minnesota lipopolysaccharides (LPS). Her symptoms of parkinsonism worsened steadily because of the chronic inflammation in the central nervous system caused by the LPS (6600 pg LPS / ml cerebrospinal fluid). Damages to the substantia nigra and cerebral cortex were shown by positron emission tomographies. Treatment with 50 mg dehydroepiandrosterone (DHEA) every other morning or with 0.35 mg 17ß-estradiol clearly improved the rigidity, stiffness, and the missing arm swing on the left side during walking without any anti-parkinsonian agents. The patient also had a good response to 275 mg levodopa, which was reduced to 200 mg (in combination with 50 mg DHEA every second day) without a deterioration of symptoms. The anti-inflammatory property of DHEA was shown by reduced inflammation-mediated nerve pain.
Parkinson's disease (PD) is a specific degeneration of dopaminergic neurons in the substantia nigra (SN). 1 Many cases of PD are accompanied by general brain inflammation with a dramatic proliferation of reactive amoeboid macrophages and microglia in the SN.1 At the same time in the SN of PD patients it has been described an increased density of glial cells expressing different pro-inflammatory cytokines as tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and interferon gamma (IFN-y).1
Bacterial endotoxins (LPS) are part of the outer cell wall of Gram negative bacteria (see figure 1). LPS elicit multiple acute pathophysiological effects such as fever, lethality, Shwartzman reactivitiy, macrophage and B-lymphocyte activation, and other activities by animals and humans.2,3 Small doses of LPS injected intravenously induce sepsislike symptoms and activate important inflammatory mediators such as TNF-alpha, IL-1ß, IL-6 and IL-8 whereas large doses of LPS precipitate life-threatening circulatory collapse and multiple organ failure. 4
Figure 1. Structure of the outer Membrane of
LPS is composed of a lipid component with lipid A and a polysaccharide component with inner and outer core and o-specific chain. n: the number of repeating units may vary from 0 to approximately 50. (Proteins are in grey colour).
Dehydroepiandrosterone sulfate DHEA-S,
which is generally metabolically
inactive, is the steroid precursor of estrogens circulating in the
bloodstream. As cells take DHEA-S from the blood, they reconvert it
DHEA is produced in the adrenal cortex.
High IL-6 levels are implicated as a causal factor in PD. 6 Decreased DHEA serum concentrations during aging or inflammatory diseases will be paralleled by a significant increase in IL-6 production.6 Furthermore, DHEA is able to protect mice from endotoxin shock.7
The observation of a higher incidence in PD in men compared to women has suggested a beneficial role of ovarian hormones. 8 In PD a positive association was reported between estrogen use and lower symptom severity in women with early PD not yet taking levodopa (L-dopa). 9 Estrogens may protect dopaminergic neurons against degeneration and/or stimulate the metabolism in surviving neurons to increase dopamine liberation in the striatum 10, thus ameliorating PD symptoms.
During the work of the author in a
laboratory the left thumb was injured. 1 ml aqueous solution with 10
Salmonella minnesota S-LPS (smooth-LPS) leaked out of a tube
wound. One hour later she showed first signs of illness (fever,
flu-like-symptoms, dyspnoea, headache, nausea, vomiting). These
continued the next three weeks with increasing intensity.
Three weeks after her accident she developed neurological problems (convulsions, sensory disturbances, myalgia, tremor, stiffness, rigidity, difficulties in learning and seeing etc.). PD was diagnosed first but the diagnosis wrongly changed to restless legs syndrome, stiff-man-syndrome and essential tremor.
The LPS, which has disrupted the blood-brain barrier (BBB), caused a chronic inflammation of the central nervous system (CNS) which became acute every spring-time. The symptoms of PD worsened during and after every acute phase of inflammation.
Furthermore, she had myalgia in the legs and back and dystonic cramps probably caused by the lack of dopamine, headaches caused by the rigidity of the neck, coordination disturbances, hyperaesthesia and hyperreflexia (every noise, vibration or touch led to muscle cloni).
3 years after the accident, great damage to her cerebral cortex was shown by positron emission tomography(PET) with [Fluorine-18] fluoro-2-deoxy-D-glucose. The method is described in Heiss et al. 11. In summary the reduction of glucose utilization was ca. 70% in the gyrus frontalis, ca. 80% in the gyrus prae- and postcentralis, and ca. 75% in the gyrus temporalis. The usual maximum activity of the cerebral cortex is 100%. A neuropsychological examination showed a hint of an acquired cerebral damage and a clear reduction of the cognitive capacity to processing of information.
2 years later the result of Limulus test (LAL) of the CSF was 6600 pg LPS / ml. The result of a LAL test of the serum was negative. This method for measuring endotoxin is described in Katsuya. 12
6 years after the contamination, damage to the dopaminergic neurons in the SN was shown by PET with 18F-dopa (see figure 2). The method is described in Holthoff-Detto et al.13 The results showed a substantial reduction of the decarboxylase activity in the caudate nuclei without difference of sides and a moderate reduction of the functionality in the putamen on both sides. These results had to be interpreted as a disturbance of the dopaminergic system.
Neurological state in May
Light hypomimia, language inconspicuous, walking alone possible, no difficulties in starting, length of stride light shortened, dragging of the left leg. No movement of the left arm during walking. Rigidity in the extremities and especially in the neck, cogwheel phenomenon in the elbow-joints and wrists. No spasticity, no contractures. Resting tremor on the left side, no postural or intention tremor. Coordination experiments sure. Diadochokinesia especially on the left side. No hyperkinesias, no dystonias. Cerebral nerves intact. Muscle reflexes on both sides middle lively. No pyramidal signs. Power of muscles normal. No trophic disturbances of the muscles. No sensory disturbances. Fine motor skills restricted, general retardation of movements. Specimen of handwriting: light artefacts of tremor, tendency of micrography. EEG inconspicuous.
Figure 2. Positron emission tomogram with F-Dopa
Treatment with DHEA
I.N. is 1.75 m tall and has a body weight of 60 kg.
Six years after her accident she took her first dose of 50 mg DHEA one day at 4.30 p.m. She was not treated with L-dopa or other anti-parkinsonian drug that time. She noticed the first effect of DHEA at 8.00 p.m. It was a very warm feeling in the legs and a release of the tension and rigidity in the muscles of my legs. She could sit relaxed with the feet completely on the floor (no cramping toes and feet any longer). At 9.00 p.m. she was able to move her left arm during walking for the first time. It was easier for her to stand up from a chair. The whole body was more relaxed and she could move more easily. These positive effects continued during the next day. At the second day she took 50 mg again at 4.30 p.m. and she noticed the positive effects one hour later. After two weeks taking 50 mg DHEA daily she began to take it every other evening. The effect of one dose DHEA seemed to be as long-lasting as 48 hours normally. When she had a lot of stress or a lot of physical movement she had to take it daily. The effects of DHEA began just 0.5 – 1.0 hour after taking. It is especially helpful against the rigidity and stiffness. She noticed an improvement in seeing contrasts.
Treatment with L-dopa
Two months later she was treated in a special clinic for PD. The neurologists began to treat her with increasing doses of L-dopa. Up to a dose of 50 mg L-dopa three times daily the effect of L-dopa was very poor. It means that she was not able to move her left arm during walking and she was very stiff and rigid especially in the legs. At the dose of 75 mg L-dopa three times daily and 50 mg L-dopa retard to the night her symptoms improved dramatically. She could move and walk normally. Especially noticeable was the slowly disappearance of the greatest rigidity in the neck. The cramp attacks, myocloni, hyperaesthesia and hyperreflexia also disappeared.
Treatment with L-dopa and DHEA
From now on she took 50 mg DHEA every other morning together with the daily dose of 275 mg L-dopa. But she did not notice any direct effect from DHEA on the PD symptoms at this dose of L-dopa. When she reduced the dose of L-dopa to 50 mg three times daily she noticed the effect of DHEA again but had not sufficient effects of the L-dopa. A single dose of 75 mg L-dopa was the lowest effective dose of L-dopa. But she could reduce the daily dose of 275 mg L-dopa to 225 mg L-dopa during taking the DHEA and half a year later to 200 mg L-dopa. During the last year she had to reduce the dose of DHEA from 50 mg every other morning to twice a week because of light acne as a negative side effect.
Table 1. Effects of DHEA and L-dopa on the
symptoms of PD
The table shows the daily dose of L-dopa and DHEA (every second day) in course of the months and the effects of the medicine on symptoms of rigidity, walking abilities and muscle pains.
|Month||8.00 a.m.||0.30 p.m.||6.00 p.m.||10.00 p.m.||Rigidity||Walking abilities||Muscle pains|
|1-2||-||-||50 mg DHEA (every 2nd day)||-||+||+||+|
|3||50 mg L-dopa||50 mg L-dopa||50 mg L-dopa||-||0||0||0|
|3||50 mg L-dopa||50 mg L-dopa||50 mg L-dopa
+50 mg DHEA (every 2nd)
|3||75 mg L-dopa||75 mg L-dopa||75 mg L-dopa||50 mg L-dopa retard||++||++||++|
|3||75 mg L-dopa + 50 mg DHEA (every 2nd)||75 mg L-dopa||75 mg L-dopa||50 mg L-dopa retard||++||++||++|
|4-10||75 mg L-dopa + 50 mg DHEA (every 2nd)||75 mg L-dopa||75 mg L-dopa||-||++||++||++|
|11-18||75 mg L-dopa + 50 mg DHEA (every 2nd)||-||75 mg L-dopa||50 mg L-dopa
0: no changes of symptoms
+: light improvement of symptoms
++: strong improvement of symptoms
Treatment with estrogen
First she took 0.03 mg 17ß-estradiol together with the daily dose of 200 mg L-dopa for a few days but she had to stop it because of bad headaches and migraine as a negative side effect. She did not notice a direct effect of the 17ß-estradiol.
Secondly she took 0.4 mg 17ß-estradiol without L-dopa. After 30-45 min the rigidity and pains disappeared in her muscles. It was exactly the same effect as with a dose of 50 mg DHEA.
A dose of 0.3 mg 17ß-estradiol was completely ineffective. The lowest effective dose was 0.35 mg. She tested it on different days of the month but it was not influenced by the variation of the natural level of estrogen.
Anti-inflammatory and neuroprotective effect of
Three months after starting the treatment with DHEA she was suffering from an acute phase of inflammation of the nervous system again. These phases began with increased body temperature (+1°C - +1.5°C) and acute pain in the legs. Later the back, especially the spinal nerves, hurt, so that every breath was painful. At the end the CNS was inflamed with acute deterioration of the symptoms of PD among other symptoms. A daily dose of 100 mg DHEA was effective against the inflammation because 30-45 min after taking the DHEA the neuralgic pain disappeared abruptly for 3-4 hours.
The DHEA showed a further very positive effect. After recovering from this bad phase, the symptoms of PD were no stronger than before this acute phase of inflammation. And she has been stable since now. The symptoms of PD were not changed to the worse.
Furthermore, the permanent difficulties in learning, short-time memory, and spatial orientation because of the damages of the cerebral cortex caused by the LPS have been improving a lot after this last phase of heavy inflammation of the CNS.
The patient described in the study presented the first case of LPS-induced parkinsonism.
The PD started three weeks after a contamination with 10 µg Salmonella minnesota S-LPS. The first symptoms described (fever, flu-like-symptoms, dyspnoea, headache, nausea, vomiting) are typical for a poisoning with LPS.3 Many humans are exposed to 10 µg LPS or higher doses during sepsis and septic shock. The BBB becomes leaky in a patchy manner within the first few hours of sepsis.14 In this case, the LPS disrupted the BBB and is still in the CNS in this case (see the result of LAL test). The LPS binding to the neurons caused an inflammation of the brain with increasing damages to the substantia nigra and cerebral cortex (see the results of PET’s). Some cases of PD are associated to head trauma and encephalitis, suggesting an inflammatory component of this disease. Inflammatory stimulus, such as LPS, has diverse effects on the cells of the CNS.1 Thus, astrocytes and microglia have been shown to secrete cytokines.1 A single injection of LPS into rat SN produced a strong inflammatory response which leads to permanent damage of the dopaminergic neurons.1 In our case, LPS binding to the neurons caused an inflammation of the brain with increasing damages to the substantia nigra and cerebral cortex (see the results of PET's).
DHEA is an anti-inflammatory hormone. The mechanism of action of DHEA are direct inhibition of nuclear factor-kappa B (NF-kB) transfer to the nucleus, inhibition of NF-kB and the nuclear factor AP-1 binding to the DNA leading to the inhibition of cytokine secretion (TNF, IL-6, IL-4, IL-10), and anti-inflammatory effects via downstream testosterone and estrogens. 15 DHEA showed its anti-inflammatory property by stopping the inflammation-mediated nerve pain for hours. This pain relieving effect was induced by a daily dose of 100 mg DHEA without negative side effects. 50 mg DHEA were not sufficient. DHEA reduced the reaction of the immune system to LPS. DHEA is able to protect mice from endotoxin shock 7 The protective effect of DHEA is due to an inhibition of macrophage TNF-alpha release, thereby preventing the host from the deleterious effects of this cytokine. 16
DHEA is very effective because it stimulated not only the production of dopamine through the increased synthesis of estrogen but also reduced the effect of inflammation on the dopaminergic neurons so that the less inflamed neurons are able to produce more dopamine. Another indication for the role of inflammation was that even low doses of the glucocorticoid prednisolone (2.5 – 5 mg) also improved the symptoms of PD although not as much as DHEA. This is probably due because the presumable prodopaminergic effect of DHEA is missing in glucocorticoids. Probably the DHEA would be probably less effective if the chronic LPS-induced inflammation was not the main cause of the degeneration and dysfunction of the dopaminergic neurons in the SN.
Estrogen may also inhibit TNF, IL-2 and IL-6 15. Whether DHEA itself or the downstream steroids are the immunomodulatory effector hormones in target cells is not known. 17 A direct immunomodulatory effect of DHEA mediated via cellular DHEA receptors has been suggested. 16 The activation of these receptors, which presence has been demonstrated in murine and human lymphocytes and macrophages, by DHEA led to alterations of cellular cytotoxicity and of IL-1 and IL-2 release in vitro.16
The role of estrogen in PD is
controversial, with some studies suggesting a
prodopaminergic effect and others suggesting an antidopaminergic
A positive association between estrogen use and lower symptom severity was found in women with early PD not yet taking L-Dopa 9. Women taking estrogen had milder PD. 9 Estrogen could help motor performances of post-menopausal PD patients. 18
Estrogen can stimulate dopamine synthesis by directly enhancing striatal tyrosine hydroxylase activity and has both presynaptic and postsynaptic effects. 18 It also indirectly affects the nigrostriatal system via opioid, glutamatergic and GABAergic systems. 18 Estrogen can downregulate human catechol-o-methyl transferase COMT transcription, protein synthesis and activity via estrogen receptors, as these effects can be blocked by a specific estrogen-receptor antagonist. 18)
The dose of 0.35 mg 17-ß-estradiol is much too high of a regular treatment of a young woman before the menopause (in comparison: oral contraceptive only contains ca. 0.015 mg – 0.035 mg 17-ß-estradiol). But lower doses are not effective on the symptoms of PD in this described case. Estrogens readily cross the BBB 19 but perhaps the amount of 17-ß-estradiol getting to the brain is too small. So the treatment was continued with 50 mg DHEA every other morning.
A simultaneous treatment with DHEA and L-dopa allowed a reduction of the dose of L-dopa from 275 mg to 200 mg. L-dopa is transported about the BBB and converted to dopamine by the enzyme dopa decarboxylase. L-dopa cannot induce a reduction of the inflammation of the dopaminergic neurons so a combination of L-dopa and DHEA may be useful. The presence of activated microglia in PD substantia nigra, together with increased levels of a number of cytokines, including TNF-alpha, interferon-g and IL-1b, suggest an inflammatory aspect. The presence of activated microglia and the upregulation of cytokines in PD may suggest a role for anti-inflammatory or immunomodulatory agents. 20 This anti-inflammatory agent may be DHEA. So the effect of DHEA in female PD patients especially before the menopause should be investigated.
Estrogen may be preventing free radical damage, since its role as an antioxidant has been proposed. 21 Estrogen confers neuroprotection. 18 During the last 18 months taking DHEA the symptoms of PD were not deteriorated in spite of one acute phase of inflammation.
Glucose utilization is diminished in the cerebral cortex of I.N. (see the PET with [Fluorine-18] fluoro-2-deoxy-D-glucose). Glucose ingestion improves cognitive performance in Alzheimer’s disease patients, and estrogen augments cerebral glucose utilization and increase cerebral blood flow. 19 Estrogen may improve cognitive impairment. 22 The treatment with DHEA led to an improvement of short-time memory and learning. These deficits have been evaluated by neuropsychological examination.
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This page was edited on October, 27th
Last update: May, 11th 2010.