U.S. patent application number 14/892287 was filed with the patent office on 2016-06-16 for treatment or prevention of non-inflammatory neuronal damage from brain trauma and strokes using menthol, linalool and/or icilin.
The applicant listed for this patent is NESTEC S.A.. Invention is credited to Susana Camacho, Johannes Le Coutre, Henry Markram, Stephanie Michlig Gonzalez, Maurizio Pezzoli.
Application Number | 20160166570 14/892287 |
Document ID | / |
Family ID | 50819728 |
Filed Date | 2016-06-16 |
United States Patent
Application |
20160166570 |
Kind Code |
A1 |
Camacho; Susana ; et
al. |
June 16, 2016 |
TREATMENT OR PREVENTION OF NON-INFLAMMATORY NEURONAL DAMAGE FROM
BRAIN TRAUMA AND STROKES USING MENTHOL, LINALOOL AND/OR ICILIN
Abstract
Compositions for prevention or treatment of non-inflammatory
neuronal damage from brain trauma and strokes are provided, and the
compositions contain a therapeutically effective amount of a
compound selected from the group consisting of Menthol, Linalool,
Icilin and combinations thereof. Methods for treatment or
prevention of non-inflammatory neuronal damage from brain trauma
and strokes are also provided, and the methods include
administering such compositions.
Inventors: |
Camacho; Susana; (Lausanne,
CH) ; Michlig Gonzalez; Stephanie; (Le Mont-sur
-Lausanne, CH) ; Le Coutre; Johannes; (Pully, CH)
; Markram; Henry; (Lausanne, CH) ; Pezzoli;
Maurizio; (Lausanne, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NESTEC S.A. |
Vevey |
|
CH |
|
|
Family ID: |
50819728 |
Appl. No.: |
14/892287 |
Filed: |
May 23, 2014 |
PCT Filed: |
May 23, 2014 |
PCT NO: |
PCT/EP2014/060637 |
371 Date: |
November 19, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61827232 |
May 24, 2013 |
|
|
|
Current U.S.
Class: |
514/274 ;
514/729; 514/739 |
Current CPC
Class: |
A23V 2002/00 20130101;
A23L 33/10 20160801; A61K 31/513 20130101; A61P 25/00 20180101;
A61K 31/045 20130101; A61P 43/00 20180101; A61P 9/10 20180101; A61P
9/00 20180101; A61K 31/045 20130101; A61K 2300/00 20130101; A61K
31/513 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 31/045 20060101 A61K031/045 |
Claims
1. A method for treating non-inflammatory neuronal damage from a
condition selected from the group consisting of brain trauma, a
stroke and a combination thereof, comprising administering to an
individual having such damage a composition comprising a
therapeutically effective amount of a compound selected from the
group consisting of Menthol, Linalool, Icilin and combinations
thereof.
2. The method of claim 1 wherein the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
3. A method for preventing non-inflammatory neuronal damage from a
condition selected from the group consisting of brain trauma, a
stroke and a combination thereof, comprising administering to an
individual having the condition a composition comprising a
therapeutically effective amount of a compound selected from the
group consisting of Menthol, Linalool, Icilin and combinations
thereof.
4. The method of claim 3 wherein the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
5. A method for preventing non-inflammatory neuronal apoptosis from
a condition selected from the group consisting of brain trauma, a
stroke and a combination thereof, comprising administering to an
individual a composition comprising a therapeutically effective
amount of a compound selected from the group consisting of Menthol,
Linalool, Icilin and combinations thereof.
6. The method of claim 5 wherein the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
7. A method for preventing non-inflammatory neuronal necrosis from
a condition selected from the group consisting of brain trauma, a
stroke and a combination thereof, comprising administering to an
individual having the condition a composition comprising a
therapeutically effective amount of a compound selected from the
group consisting of Menthol, Linalool, Icilin and combinations
thereof.
8. The method of claim 7 wherein the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
9. A method for providing neuroprotection to an individual in need
of same comprising administering a composition comprising a
therapeutically effective amount of a compound selected from the
group consisting of Menthol, Linalool, Icilin and combinations
thereof.
10. The method of claim 9 wherein the composition is a
medicament.
11. The method of claim 9 wherein the composition is a food
product.
12. The method of claim 11 wherein the food product comprises a
component selected from the group consisting of protein,
carbohydrate, fat and combinations thereof.
13. The method of claim 9 wherein the composition is a supplement
to a food product.
Description
BACKGROUND
[0001] The present disclosure generally relates to methods and
compositions for prevention or treatment of non-inflammatory
neuronal damage from brain trauma and strokes. More specifically,
the present disclosure relates to compositions comprising at least
one of Menthol, Linalool or Icilin and further relates to methods
comprising administering such compositions.
[0002] During brain injury, glutamate accumulation leads to
overstimulation of postsynaptic glutamate receptors with
intracellular Ca.sup.2+ overload and neuronal cell death. For
example, even a brief ischemic stroke may trigger complex cellular
events that lead to both apoptotic and necrotic neuronal cell death
in a progressive manner Therefore, glutamate antagonists are common
neuroprotective treatments. These antagonists inhibit the binding
of glutamate to NMDA receptors such that accumulation of Ca.sup.2+
and therefore excitotoxicity can be avoided. However, use of
glutamate antagonists presents a huge obstacle because the
treatment interferes with the normal action of glutamate under
standard conditions. A number of glutamate antagonists have been
explored as options in central nervous system (CNS) disorders, but
many are found to lack efficacy or have intolerable side
effects.
[0003] There is a clear and persisting need to achieve
neuroprotection and prevent and treat non-inflammatory neuronal
damage from brain trauma and strokes.
SUMMARY
[0004] The present inventors surprisingly and unexpectedly found
that several active compounds from spices can depress neuronal
activity in the neocortex and the amygdale. These compounds are
Menthol and Linanool which are transient receptor potential M8
(TRPM8) channel agonists. The present inventors discovered the same
effect with Icilin, a synthetic super-agonist of the TRPM8 ion
channel, even though the structure of Icilin is not related to
Menthol.
[0005] Accordingly, in a general embodiment, the present disclosure
provides a method for treating non-inflammatory neuronal damage
from a condition selected from the group consisting of brain
trauma, a stroke and a combination thereof is provided. The method
comprises administering to an individual having such damage a
composition comprising a therapeutically effective amount of a
compound selected from the group consisting of Menthol, Linalool,
Icilin and combinations thereof.
[0006] In a related embodiment, the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
[0007] In another embodiment, a method for preventing
non-inflammatory neuronal damage from a condition selected from the
group consisting of brain trauma, a stroke and a combination
thereof is provided. The method comprises administering to an
individual having the condition a composition comprising a
therapeutically effective amount of a compound selected from the
group consisting of Menthol, Linalool, Icilin and combinations
thereof.
[0008] In a related embodiment, the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
[0009] In another embodiment, a method for preventing
non-inflammatory neuronal apoptosis from a condition selected from
the group consisting of brain trauma, a stroke and a combination
thereof is provided. The method comprises administering to an
individual a composition comprising a therapeutically effective
amount of a compound selected from the group consisting of Menthol,
Linalool, Icilin and combinations thereof.
[0010] In a related embodiment, the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
[0011] In another embodiment, a method for preventing
non-inflammatory neuronal necrosis is provided. The method
comprises administering to an individual having the condition a
composition comprising a therapeutically effective amount of a
compound selected from the group consisting of Menthol, Linalool,
Icilin and combinations thereof.
[0012] In a related embodiment, the composition is selected from
the group consisting of a medicament, a food product and a
supplement to a food product.
[0013] In another embodiment, a composition for neuroprotection
against non-inflammatory neuronal damage from a condition selected
from the group consisting of brain trauma, a stroke and a
combination thereof is provided. The composition comprises a
therapeutically effective amount of a compound selected from the
group consisting of Menthol, Linalool, Icilin and combinations
thereof.
[0014] In a related embodiment, the composition is a
medicament.
[0015] In a related embodiment, the composition is a food product.
The food product can comprise a component selected from the group
consisting of protein, carbohydrate, fat and combinations
thereof.
[0016] In a related embodiment, the composition is a supplement to
a food product.
[0017] In a related embodiment, the composition is a supplement to
a food product.
[0018] An advantage of the present disclosure is to provide
neuroprotection against non-inflammatory neuronal damage from brain
trauma and strokes more effectively and/or more safely than
glutamate antagonists.
[0019] Another advantage of the present disclosure is to prevent or
treat non-inflammatory neuronal damage from brain trauma and
strokes.
[0020] Still another advantage of the present disclosure is to
prevent or treat non-inflammatory neuronal damage from brain trauma
and strokes with compounds that can be easily and safely used in
food products.
[0021] Yet another advantage of the present disclosure is to
prevent or treat non-inflammatory neuronal damage from brain trauma
and strokes by targeting the pre-synaptic phase of neuronal
firing.
[0022] An additional advantage of the present disclosure is to
prevent or treat non-inflammatory neuronal damage from brain trauma
and strokes by targeting the pre-synaptic phase of neuronal firing
while reducing the possibility of excitotoxicity.
[0023] Another advantage of the present disclosure is to prevent or
treat non-inflammatory neuronal damage from brain trauma and
strokes with naturally-occurring compounds that can be found in
spices.
[0024] Still another advantage of the present disclosure is to
prevent or treat non-inflammatory neuronal damage from brain trauma
and strokes with tolerable side effects or no side effects.
[0025] Yet another advantage of the present disclosure is to
prevent or treat non-inflammatory neuronal damage from brain trauma
and strokes without interfering with the normal action of glutamate
under standard conditions
[0026] Additional features and advantages are described herein, and
will be apparent from, the following Detailed Description and the
Figures.
BRIEF DESCRIPTION OF THE FIGURES
[0027] FIG. 1 shows the chemical structures of compounds that can
be used in embodiments of the composition according to the present
disclosure.
[0028] FIG. 2 shows charts of whole cell, current clamp recordings
in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice)
in the absence (control) and presence of the TRPM8 ligands
Linalool, Icilin or Menthol.
[0029] FIG. 3 shows a chart of whole cell, current clamp recordings
in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice)
with increasing concentration of gabazine (GABA A blocker) applied
extracellularly during recordings of 5 min each (washout 10
min).
[0030] FIG. 4 shows a chart of whole cell, current clamp recordings
in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice)
showing enhanced detail of a burst.
[0031] FIG. 5 shows a chart of whole cell, current clamp recordings
in a Lateral Amygdala glutamatergic neuron (in a mouse brain slice)
with increasing concentration of gabazine (GABA A blocker) applied
extracellularly during recordings of 5 min each (washout 10 min.)
while 10 minutes previous to and during the exposure of the
different concentrations of gabazine, 250 .mu.M menthol was also
applied extracellularly.
DETAILED DESCRIPTION
[0032] All percentages expressed herein are by weight of the total
weight of the composition unless expressed otherwise. When
reference is made to the pH, values correspond to pH measured at
25.degree. C. with standard equipment. As used in this disclosure
and the appended claims, the singular forms "a," "an" and "the"
include plural referents unless the context clearly dictates
otherwise. As used herein, "about" is understood to refer to
numbers in a range of numerals. Moreover, all numerical ranges
herein should be understood to include all integers, whole or
fractions, within the range. The food composition disclosed herein
may lack any element that is not specifically disclosed herein.
Thus, "comprising" includes "consisting essentially of" and
"consisting of."
[0033] As used herein, "neuroprotection" refers to promotion of
neuronal survival, promotion of neuronal repair, limiting neuronal
oxidative stress, and/or limiting cell damage. "Cell damage" is any
impairment of function in a neuron, including cell death. "Cell
death" includes apoptosis and necrosis as non-limiting examples.
"Non-inflammatory" means unrelated to or not caused by neurogenic
inflammation.
[0034] "Prevention" includes reduction of risk and/or severity of
non-inflammatory neuronal damage from brain trauma and strokes. The
terms "treatment," "treat" and "to alleviate" include both
prophylactic or preventive treatment (that prevent and/or slow the
development of a targeted pathologic condition or disorder) and
curative, therapeutic or disease-modifying treatment, including
therapeutic measures that cure, slow down, lessen symptoms of,
and/or halt progression of a diagnosed pathologic condition or
disorder; and treatment of patients at risk of contracting a
disease or suspected to have contracted a disease, as well as
patients who are ill or have been diagnosed as suffering from a
disease or medical condition. The term does not necessarily imply
that a subject is treated until total recovery. The terms
"treatment" and "treat" also refer to the maintenance and/or
promotion of health in an individual not suffering from a disease
but who may be susceptible to the development of an unhealthy
condition. The terms "treatment," "treat" and "to alleviate" are
also intended to include the potentiation or otherwise enhancement
of one or more primary prophylactic or therapeutic measure. The
terms "treatment," "treat" and "to alleviate" are further intended
to include the dietary management of a disease or condition or the
dietary management for prophylaxis or prevention a disease or
condition. A treatment can be patient- or doctor-related.
[0035] As used herein, a "therapeutically effective amount" is an
amount that prevents a deficiency, treats a disease or medical
condition in an individual or, more generally, reduces symptoms,
manages progression of the diseases or provides a nutritional,
physiological, or medical benefit to the individual.
[0036] "Animal" includes, but is not limited to, mammals, which
includes but is not limited to, rodents, aquatic mammals, domestic
animals such as dogs and cats, farm animals such as sheep, pigs,
cows and horses, and humans. Where "animal," "mammal" or a plural
thereof is used, these terms also apply to any animal that is
capable of the effect exhibited or intended to be exhibited by the
context of the passage. As used herein, the term "patient" is
understood to include an animal, especially a mammal, and more
especially a human that is receiving or intended to receive
treatment, as treatment is herein defined. While the terms
"individual" and "patient" are often used herein to refer to a
human, the present disclosure is not so limited. Accordingly, the
terms "individual" and "patient" refer to any animal, mammal or
human, having or at risk for a medical condition that can benefit
from the treatment.
[0037] "Food product" and "food composition," as used herein, are
understood to include any number of optional additional
ingredients, including conventional food additives, for example one
or more proteins, carbohydrates, fats, acidulants, thickeners,
buffers or agents for pH adjustment, chelating agents, colorants,
emulsifiers, excipients, flavor agents, minerals, osmotic agents, a
pharmaceutically acceptable carrier, preservatives, stabilizers,
sugars, sweeteners, texturizers and/or vitamins. The optional
ingredients can be added in any suitable amount.
[0038] As set forth above, the present inventors surprisingly and
unexpectedly found that several active compounds from spices can
depress neuronal activity in neocortex and amygdale. These
compounds are Menthol and Linanool which are transient receptor
potential M8 (TRPM8) channel agonists. The present inventors
discovered the same effect with Icilin, a synthetic super-agonist
of the TRPM8 ion channel, even though the structure of Icilin is
not related with Menthol; nevertheless, Icilin produces an extreme
sensation of cold both in humans and animals. These natural
compounds reduce neuronal excitability by 1) increasing the
threshold to trigger an action potential and consequently
increasing the amount of current required to trigger an action
potential in the neocortex; and 2) abortion of action potentials at
higher stimulation levels, most likely related to the use-dependent
block of Na.sup.+ channels in the neocortex and lateral amygdale.
These active compounds change the firing patterns especially at
higher stimulation levels where a progressive and dramatic
reduction of the action potential (APs) amplitude occurs until
complete abortion of APs.
[0039] Without wishing to be bound by theory, the inventors believe
that the mechanism underlying the selected active compounds of
spices, namely Menthol, Linanool and Icilin, solves two main
problems compared to neuroprotective glutamate antagonists: 1)
Menthol, Linanool and Icilin target a presynaptic phase of APs,
decreasing activity and diminishing glutamate release, which
reduces drastically the possibility of reaching excitotoxicity
levels; and 2) Menthol, Linanool and Icilin act stronger in the
high stimulation context. In contrast to glutamate antagonists that
typically inhibit the binding of glutamate to NMDA receptors,
Menthol, Linanool and Icilin decrease neuronal activity, and target
the pre-synaptic phase of the firing to reduce the possibilities of
excitotoxicity one step earlier.
[0040] Accordingly, the composition provided by the present
disclosure comprises a therapeutically effective amount of at least
one of Menthol, Linalool or Icilin. The Menthol, Linalool and/or
Icilin can be therapeutically effective to provide neuroprotection
against non-inflammatory neuronal damage from brain trauma and
strokes. Furthermore, Menthol, Linalool and/or Icilin can be
therapeutically effective to treat or prevent non-inflammatory
neuronal damage from brain trauma and strokes. For example, the
composition comprising at least one of Menthol, Linalool or Icilin
can be administered to an individual having brain trauma and/or a
stroke to prevent or treat non-inflammatory neuronal damage from
the brain trauma and/or stroke. The neuroprotection, the treatment
or the prevention can reduce or prevent neuronal cell damage,
including cell death, such as neuronal apoptosis and/or neuronal
necrosis, for example. In an embodiment, the composition comprising
a therapeutically effective amount of at least one of Menthol,
Linalool or Icilin is administered to a human.
[0041] Each of Menthol, Linalool and/or Icilin can be administered
to the individual in a daily amount of 0.0015 mg/kg of body weight
to 400 mg/kg of body weight, preferably 0.1 mg/kg of body weight to
300 mg/kg of body weight, more preferably 1.0 mg/kg of body weight
to 200 mg/kg of body weight, and most preferably 10.0 mg/kg of body
weight to 100 mg/kg of body weight. For example, each of Menthol,
Linalool and/or Icilin can be administered to the individual in a
daily amount of 0.0015 mg/kg of body weight to 0.01 mg/kg of body
weight, 0.01 mg/kg of body weight to 0.1 mg/kg of body weight, 0.1
mg/kg of body weight to 1.0 mg/kg of body weight, 1.0 mg/kg of body
weight to 10.0 mg/kg of body weight, 10.0 mg/kg of body weight to
100.0 mg/kg of body weight, 100.0 mg/kg of body weight to 200.0
mg/kg of body weight, 200.0 mg/kg of body weight to 300.0 mg/kg of
body weight, or 300.0 mg/kg of body weight to 400.0 mg/kg of body
weight.
[0042] The composition comprising at least one of Menthol, Linalool
or Icilin may be a medicament, a food product or a supplement to a
food product. The supplement may be in the form of tablets,
capsules, pastilles or a liquid, for example. The supplement may
further contain protective hydrocolloids (such as gums, proteins,
modified starches), binders, film forming agents, encapsulating
agents/materials, wall/shell materials, matrix compounds, coatings,
emulsifiers, surface active agents, solubilizing agents (oils,
fats, waxes, lecithins or the like), adsorbents, carriers, fillers,
co-compounds, dispersing agents, wetting agents, processing aids
(solvents), flowing agents, taste masking agents, weighting agents,
jellifying agents and gel forming agents. The supplement may also
contain conventional pharmaceutical additives and adjuvants,
excipients and diluents, including, but not limited to, water,
gelatin of any origin, vegetable gums, ligninsulfonate, talc,
sugars, starch, gum arabic, vegetable oils, polyalkylene glycols,
flavoring agents, preservatives, stabilizers, emulsifying agents,
buffers, lubricants, colorants, wetting agents, fillers, and the
like.
[0043] The supplement can be added in a product acceptable to the
consumer as an ingestible carrier or support. Non-limiting examples
of such carriers or supports are a pharmaceutical, a food
composition, and a pet food composition. Non-limiting examples for
food and pet food compositions are milks, yogurts, curds, cheeses,
fermented milks, milk-based fermented products, fermented cereal
based products, milk-based powders, human milks, preterm formulas,
infant formulas, oral supplements, and tube feedings.
EXAMPLES
[0044] The following non-limiting examples present scientific data
developing and supporting the concept of treatment or prevention of
non-inflammatory neuronal damage from brain trauma and strokes.
[0045] A mouse brain slice was used to study the damage from
Menthol, Linalool and Icilin. The amygdaloid complex is located
within the medial temporal lobe in neocortex and amygdala. The
lateral and basolateral nuclei of the amygdaloid complex receive
sensory information from cortical and thalamic structures, process
the information, and then transmit the information, either directly
or through the basal nucleus, to the central nucleus. For
experimental analysis of neuronal activity, synaptic responses from
the basolateral complex can be evoked electrically using
electrodes, and the action potentials can be measured.
[0046] FIG. 2 shows recordings in the absence of Menthol, Linalool
or Icilin (control) and recordings in the presence of Menthol,
Linalool or Icilin. A square pulse of 2.5s was applied at high
depolarization of membrane potential (approximately -30 mV). The
recordings show that, in the presence of the TRPM8 ligands at high
depolarization levels, inactivation of the sodium fast channels
happens sooner relative to control, avoiding further neuronal
firing.
[0047] FIG. 3 shows recordings in increasing concentrations of
gabazine, a GABA A blocker, applied extracellularly during
recordings of 5 minutes each with 10 minute washout. As shown,
neurons spontaneously present action potential bursts due to
massive presynaptic discharges. FIG. 4 depicts enhanced detail of
one of the bursts and shows that serial action potentials can be
observed in a single burst. For comparison to FIG. 3, FIG. 5 shows
recordings under the same conditions, namely increasing
concentrations of gabazine applied extracellularly during
recordings of 5 minutes each with 10 minute washout, except that in
FIG. 5, Menthol 250 .mu.M was applied extracellularly at 10 minutes
previous to and during the exposure of the different concentrations
of gabazine. As illustrated in the figure, neurons show a complete
absence or a strongly decreased presence of spontaneous bursts
(compare FIG. 5 to FIG. 3).
[0048] These experimental results demonstrate that Menthol,
Linalool and Icilin increase the threshold to trigger an action
potential and consequently increase the amount of current required
to trigger an action potential in the neocortex, and also abort
action potentials at higher stimulation levels.
[0049] It should be understood that various changes and
modifications to the presently preferred embodiments described
herein will be apparent to those skilled in the art. Such changes
and modifications can be made without departing from the spirit and
scope of the present subject matter and without diminishing its
intended advantages. It is therefore intended that such changes and
modifications be covered by the appended claims.
* * * * *