Leucine Enkephalin as Treatment of Septic Polyneuropathy and Encephalopathy
Ines Niehaus
Comments to: Ines_Niehaus@gmx.de
Poster presentation at the
4th International Congress "Sepsis and Multiorgan Dysfunction"
Weimar Sepsis Update 2009
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This is the first case report of effective treatment of long-term neurological sequelaes
of sepsis with leucine enkephalin (LE). The 37 years old female patient is suffering from
lipopolysaccharide-induced polyneuropathy, encephalopathy and parkinsonism 14 yrs after
sepsis. Acute and long-term neurological sequelaes of sepsis occur in up to 70% of the patients.
LE is used in orally administered doses of 1 micromol every third day. A lot of neurological
symptoms like reduced sensibility, weakness, walking abilities, concentration, bradykinesia
and rigidity are markedly improved 5 hours after taken one dose of LE and also after months.
The neurotransmitter LE with the amino acid sequence tyrosine, glycine, glycine, phenylalanine,
leucine is neuro- and cytoprotective. LE increases the cerebral blood and lymphatic flow.
The Russian synthetic LE product Dalargin is helpful in treating postoperative patients with
multiorgan failure.
LE stimulates the neurotransmitter release of primary sensory neurons. Physiological nmol to
pmol concentration of LE prolongs the action potential duration of primary sensory neurons by
binding to stimulatory G-protein coupled delta-opioid receptors of presynaptic terminals with
elevation of cAMP levels and stimulation of calcium influx. The glutamate release is increased
in the synaptic cleft. LPS is blocking the LE stimulatory effect by binding to
alpha2-delta2-subunits
of voltage-gated calcium channels and to delta-opioid receptors. Increased levels of LE by oral
uptake are able to restore the function of LPS-blocked G-protein coupling to delta-opioid receptors
by causing a new palmitoylation signal to cysteine 333.
Fig. 1: Structure of the Gram negative membrane with calcium-LPS-complexes
Leucine Enkephalin:
Leucine enkephalin is a pentapeptide (Fig. 2) with the amino acid
sequence of
tyr-gly-gly-phe-leu.
Fig. 2: Structure of Leucine Enkephalin
Tab.1 : Effects of Leucine Enkephalin (LE) in Humans
Nervous System |
Immune System |
neurotransmitter |
synthetic LE
Dalargin prevents infection in cardiosurgical pat. |
opioid peptide |
Dalargin reduces
respiratory distress syndrome severity
12 |
binds to
G-protein coupled delta-opioid receptors |
Dalargin useful
in treating postoperative multiorgan failure
11 |
inhibitory and
stimulatory effects on neurotransmitter release |
improves wound
healing in patients with severe burn injuries |
primary afferent
nerves increase activity in spinothalamic tract |
antioxidative
properties with e. g. protection of lung and liver |
stimulatory
effect on primary sensory neurons6 |
oxidative damage
of organ transplants reduced |
stimulatory
effect blocked by ganglioside GM1 antibodies |
reduces
LPS-induced TNF-alpha
production of macrophages |
neuroprotective
in LPS-stimulated dopaminergic cell cultures |
reduces
anti-LPS-IgM-antibodies in LPS-stimulated B-cells |
neuroprotective
in femtomol conc. by inhibiting PHOX9 |
airway cells
increase cAMP with bronchodilatation |
reduction of
reactive oxygen species production in microglia |
immune cells
(T-/B-cells, macrophages) with opioid-receptors |
restores dopamine transporter loss in
methamphetamin PD |
uptaken by
immune cells to 95% |
microglia and
astrocytes express delta-opioid receptors |
produced by macrophages |
Circulation |
Processing of Leucine Enkephalin |
stimulates
peripheral and central lymph circulation |
preproenkephalin
mRNA |
improves cerebral blood flow in
brain ischemia13 |
protein
proenkephalin |
reduces high intraocular pressure |
processing in
trans-golgi-network to tyr-gly-gly-phe-leu |
antiarrythmic heart effects |
storage of LE in
80-120 nm large dense-core vesicles |
vasotonic in femtomolar concentration |
long stimulus
for release of LE in synaptic cleft |
Summary of Case Report
This is the first case report describing a treatment with leucine
enkephalin for an up to now 14 years long-lasting persistent
endotoxemia causing chronically systemic and neuronal inflammation with
septic polyneuropathy, encephalopathy and parkinsonism after one single
accidental contamination with 10 µg highly purified Salmonella
minnesota S-LPS in 1995. The LPS has not been detoxified by the body
proven by a limulus lysate assay test of the cerebrospinal fluid CSF in
2001 (6600 pg LPS/ml CSF) and by a Fourier transform infrared
spectroscopy analysis of a blood sample in 2003, which showed a high
content of 100% identified Salmonella minnesota S-LPS. Positron
emission tomography (PET) with Fluoro-Dopa showed ca. 70% loss of
dopaminergic function in the striatum in 2001. Cerebral glucose
metabolism was determined with [Fluorine-18] fluoro-2-deoxy-D-glucose
using PET in 1998. In summary the usually normal 100% 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. In 2006
electroneurography conduction studies showed conduction blocks of
sensory nerves and missing F-waves in the N. peronaeus, which is the
most sensible nerve to endotoxins in the blood of septic patients (Fig.
3).
3
4
Treatment with 1 µmol LE started in December
2008.
Fig. 3: Results of electrophysiological examinations of the 34 years old female patient 11 years after sepsis in 2006.
Tab.2 : Effects of Leucine Enkephalin Treatment on different Symptoms
Polyneuropathy |
|
Encephalopathy |
|
Parkinsonism |
|
Others |
|
|
|||
Pain |
+ |
++ |
Concentration |
++ |
++ |
Rigidity |
++ |
+ |
Myocloni |
++ |
+ |
Paraesthesia |
+ |
+ |
Tiredness |
0 |
+ |
Stiffness |
++ |
+ |
Seizures |
+ |
+ |
Numbness |
++ |
+ |
Short time memory |
++ |
+ |
Tremor |
0 |
+ |
Dysphagia |
+ |
+ |
Reduced
sensibility |
+++ |
+++ |
Long time memory |
0 |
+ |
Bradykinesia |
+++ |
++ |
Speaking Difficulties |
+ |
+ |
Weakness |
+++ |
++ |
Forgetfulness |
+ |
+ |
Cogwheel phenomena |
+++ |
+ |
General condition |
+ |
+ |
Muscle atrophy |
0 |
+ |
Velocity of
information processing |
+ |
+ |
Reduced blinking rate |
++ |
+ |
Asthma |
++ |
+ |
Walking abilities |
+++ |
++ |
Headache |
+ |
+ |
Arm swing in walking |
+++ |
++ |
|
||
Muscle power |
++ |
+ |
|
|
|
Micrography |
+ |
+ |
|
in
grey colour: effects 5 hours after 1 x 1 µmol LE |
in white
colour: |
long-term effects of LE |
||
0 |
no effect |
++ |
strong improvement of symptoms |
|
+ |
improvement of symptoms |
+++ |
very strong
improvement of symptoms |
img src="SensNeuronFertigGif.gif">
Fig. 4: LPS blocks the LE stimulatory effect in primary sensory
neurons by:
1. Binding to d-opioid-receptors with steric hindering of G-protein
coupling
2. Binding to alpha2-delta2-subunits of
voltage-gated calcium channels reducing calcium influx into the cell
3. Binding to ganglioside GM1 linked to delta-opioid-receptors by arg
192
Salmonella minnesota S-LPS was uptaken by e. g. macrophages, microglia and astrocytes, being chemically unmodified intercalated in cell membranes and Golgi-apparatus causing chronic inflammation with progressive neurodegeneration in the patient. Lipid A of LPS binds to pentapeptide sequences of B-H-P-H-B or B-H-B-H-B (B: Arg+, Lys+, h: hydrophobic amino acid, p: polar amino acid). 1 The intracellular C-terminal loop of delta-opioid-receptors is blocked by lipid A bound to lys+-pro-cys-gly-arg+ (Fig. 4) resulting in inability to couple to G-proteins with stopping of LE signals. Stimulatory Gs-protein coupled delta-opioid-receptors bind to ganglioside GM1 with arg 192. Cells without GM1 or antibody blocked GM1 like in Campylobacter jejuni infections (Guillain-Barré-Syndrome) react to LE by Go-protein coupled inhibitory signals.
How is orally administered LE effective in LPS-induced septic polyneuropathy and encephalopathy?
Polyneuropathy: LPS-blocked delta opioid receptors downregulate preproenkephalin mRNA expression with reduced LE levels. Polyneuropathy patients have very low blood LE levels. Increased levels of LE by oral uptake are able to activate blocked delta-opioid receptors 5 by causing a new palmitoylation signal to cysteine 333 (Fig. 4) with the ability of the C-terminal loop to bind to Gs-proteins again with increased levels of cAMP and increased calcium influx via voltage-gated calcium channels. The LE stimulatory signal causes expression of GM1. As the treatment with LE in the patient have long-term effects even after stopping the uptake of LE for months LE seems to start a self-propagating mechanism with reactivation of LPS-blocked delta-opioid receptors, upregulated preproenkephalin mRNA and GM1 expression leading to normalized LE levels in the nervous and immune system of the patient.
Encephalopathy: Neuroinflammation with memory impairment induced by chronic intraventricular LPS infusion was marked by completely block of voltage-gated calcium channel dependent long-term potentiation in rats’ hippocampus, 8 probably caused by binding of LPS to pentapeptide arg+-pro-arg+-tyr-arg+ of alpha 2-delta2-subunits of calcium channels (Fig. 4). LE increases the influx of calcium into cells and improves memory function. Dorsal horn ganglions are switching in inflammatory status the expression of alpha2-delta2-subunits to alpha2-delta1-subunits without LPS-binding pentapeptide. LE stimulates the cerebral blood flow 13 with improved dopamine and glucose metabolism of the patient. Ultralow fmol concentration of LE are delta-opioid-receptor independent neuroprotective by reduction of the production of reactive oxygen species in LPS-stimulated mixed microglia dopaminergic cell cultures. 9
Conclusions: This is the first case report reporting about an effective treatment of septic polyneuropathy and encephalopathy with parkinsonism with µmol doses of LE every third day. Dalargin (Russian synthetic LE) is useful in treating patients with postoperative multiorgan failures. Clinical trials with septic patients suffering from neurological sequelaes should be considered.
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Last update: May, 8th 2010.