U.S. patent number 5,234,956 [Application Number 07/949,342] was granted by the patent office on 1993-08-10 for method of preventing nmda receptor complex-mediated neuronal damage.
This patent grant is currently assigned to The Children's Medical Center Corporation. Invention is credited to Stuart A. Lipton.
United States Patent |
5,234,956 |
Lipton |
August 10, 1993 |
**Please see images for:
( Certificate of Correction ) ** |
Method of preventing NMDA receptor complex-mediated neuronal
damage
Abstract
Disclosed is a method for reducing NMDA receptor-mediated
neuronal damage in a mammal by administering to the mammal a
nitric-oxide generating compound, or a physiologically acceptable
salt thereof, in a concentration effective to cause such reduction.
Also disclosed is a method for reducing NMDA receptor-mediated
neuronal damage in a mammal by administering to the mammal
nitroprusside, nitroglycerin, or a derivative of one of those
compounds, in a concentration effective to cause such
reduction.
Inventors: |
Lipton; Stuart A. (Newton,
MA) |
Assignee: |
The Children's Medical Center
Corporation (Boston, MA)
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Family
ID: |
24766524 |
Appl.
No.: |
07/949,342 |
Filed: |
September 22, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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688965 |
Apr 19, 1991 |
|
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Current U.S.
Class: |
514/724 |
Current CPC
Class: |
A61P
9/10 (20180101); A61K 31/21 (20130101); A61P
31/18 (20180101); A61P 39/00 (20180101); A61P
31/12 (20180101); A61K 9/7023 (20130101); A61P
3/08 (20180101); A61P 43/00 (20180101); A61P
25/10 (20180101); A61P 9/00 (20180101); A61P
25/28 (20180101); A61P 37/04 (20180101); A61P
25/00 (20180101); A61P 25/16 (20180101); A61K
31/295 (20130101); A61K 31/195 (20130101); A61P
25/14 (20180101) |
Current International
Class: |
A61K
38/44 (20060101); A61K 38/43 (20060101); A61K
9/70 (20060101); A61K 31/295 (20060101); A61K
31/195 (20060101); A61K 31/21 (20060101); A61K
31/28 (20060101); A61K 31/185 (20060101); A61K
031/045 () |
Field of
Search: |
;514/724 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Garthwaite, Trends in Pharmacological Sciences, vol. 14, No. 2, pp.
60-67, 1991. .
Hope et al., Proc. Natl. Acad. Sci. USA, vol. 88, pp. 2811-2814,
Apr. 1991. .
Meldrum et al., Trends in Pharmacological Sciences, vol. 11, pp.
379-387, Sep. 1990. .
Garthwaite et al., Neuroscience, vol. 26, No. 1, pp. 321-326, 1988.
.
Merck Index, p. 858. .
Merck Index, 9th Edition, pp. 858-859, #6429 and #6429, 1976. .
Sucher et al., Neuropharmacology and Neurotoxicity 1:29-32, 1990.
.
Aizenman et al., Neuron 2:1257-1263, 1989. .
Seubert, Brain Research 492:366-370, 1990. .
Sernagor, Neuron. 2:1221-1227, 1989. .
Goldberg et al., J. Pharm. Exp. Therapeutics 245:1081-1087, 1988.
.
Davenport et al., Eur. J. Pharm. 154:73-78, 1988. .
Choi et al., J. Pharmacol. and Exp. Therapeutics 242:713-730, 1987.
.
Hahn et al., Proc. Natl. Acad. Sci. USA 85:6556-6560, 1988. .
Choi, Neuron. 1:623, 1988. .
Rothman et al., Trends Neurosci. 10:299, 1987. .
Meldrum et al., Trends Pharm. Sci. 11:379, 1990. .
Weiss et al., Science 247:1474, 1990. .
Garthwaite et al., Trends in Neurosciences 14:60, 1991. .
Hope et al., Proc. Natl. Acad. Sci. USA 88:2811, 1991. .
Aizenman et al., Neuron 5:8411-846, 1990. .
Majewska et al., Brain Res. 537:328-332, 1990. .
Levy et al., Neurosci. Letters 110:291-296, 1990..
|
Primary Examiner: Friedman; S. J.
Attorney, Agent or Firm: Fish & Richardson
Parent Case Text
This is a continuation of application Ser. No. 07/688,965, filed
Apr. 19, 1991, now abandoned.
Claims
I claim:
1. A method for reducing NMDA receptor-mediated neuronal damage in
a human comprising reducing the NMDA-mediated increase in the
intraneuronal concentration by administering to said human a
compound selected from the group consisting of: a) nitroprusside,
b) nitroglycerin, c) an NO-generating derivative of nitroprusside
or nitroglycerin, or d) a physiologically acceptable salt of a)-c),
above, in a concentration effective to cause such reduction.
2. The method of claim 1, wherein said compound is nitroprusside or
a physiologically acceptable salt thereof.
3. The method of claim 1, wherein said compound is nitroglycerine
or a physiologically acceptable salt thereof.
4. The method of claim 1, wherein said compound is nitroprusside or
an NO-generating derivative thereof.
5. The method of claim 1, wherein said compound is nitroglycerin or
an NO-generating derivative thereof.
6. The method of any of claims 1-5, wherein said human is infected
with a human immunodeficiency virus.
7. The method of claim 6, wherein said human manifests symptoms of
the AIDS related complex or acquired immunodeficiency syndrome.
8. The method of any of claims 1-5 wherein said human suffers from
a disorder selected from the group consisting of hypoxia, ischemia,
trauma, hypoglycemia, seizures, stroke, Alzheimer's disease,
Huntington's disease, or Parkinson's disease.
9. A method for controlling neuronal damage associated with a
disorder selected from the group consisting of hypoxia, ischemia,
trauma, hypoglycemia, seizures, stroke, Alzheimer's disease,
Huntington's disease, Parkinson's disease, and infection with Human
Immunodeficiency Virus (HIV),
said method comprising administering to a patient: a)
nitroglycerin, b) nitroprusside, c) an NO-generating derivative of
a) or b), or d) a physiologically acceptable salt of a)-c).
10. The method claim 9 wherein said disorder is infection with
HIV.
11. The method claim 9 wherein said disorder is hypoxia or
ischemia.
12. The method of claim 9, claim 10 or claim 11 comprising
administering nitroglycerin or a physiologically acceptable salt
thereof to said patient.
13. The method of claim 9, claim 10 or claim 11 comprising
administering nitroprusside or a physiologically acceptable salt
thereof to said patient.
Description
BACKGROUND OF THE INVENTION
This invention relates to the treatment of nervous system
disorders, particularly disorders mediated by the
N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid
receptor complex.
Glutamate has been implicated as a significant factor in the
neurotoxicity associated with hypoxic-ischemic encephalopathy,
anoxia, hypoglycemia, seizures, trauma, and several degenerative
neurological disorders such as the AIDS dementia complex and other
neurological manifestations of AIDS, Huntington's disease and
Parkinsonism (Hahn et al., Proc. Natl. Acad. Sci. USA 85:6556,
1988; Choi, Neuron 1:623, 1988; Rothman et al., Trends Neurosci.
10:299, 1987; Meldrum et al., Trends Pharm. Sci. 11:379, 1990). In
many central neurons the predominant form of this neurotoxicity
appears to be mediated by activation of the NMDA subtype of
glutamate receptor and subsequent influx of excessive Ca.sup.2+
(Choi, ibid; Weiss et al., Science 247:1474, 1990).
SUMMARY OF THE INVENTION
I have discovered that certain compounds protect neurons against
NMDA receptor-mediated neuronal damage. Specifically,
nitroglycerin, nitroprusside, and their derivatives provide such
protection. Thus, one aspect of the invention features a method for
reducing NMDA receptor complex-mediated neuronal damage in a
mammal, by administering one of the above-described compounds to
the mammal.
With regard to the compounds of the first aspect of the invention,
I do not wish to bind myself to any particular theory or mechanism
of action. However, oxidation of the NMDA receptor is known to
protect against NMDA receptor-mediated neuronal damage (see, e.g.,
PCT W091/02180). It is also known that the active species of
nitroglycerin and nitroprusside is nitric oxide (NO) (see, e.g.,
Garthwaite et al. (Trends in Neurosciences 14:60, 1991).
Accordingly, one possible mechanism for the protective effect that
I have discovered is nitric oxide-induced oxidation of the NMDA
receptor-channel complex.
Accordingly, a second aspect of the invention features a method for
reducing NMDA receptor complex-mediated neuronal damage by
administering a nitric-oxide generating compound, in a
concentration effective to cause such reduction. This second aspect
of the invention is founded on the premise that NO acts on the NMDA
receptor-channel complex to protect against NMDA receptor-mediated
damage.
In preferred embodiments of both aspects of the invention, the
mammal is a human infected with a virus affecting the nervous
system--e.g., measles or human immunodeficiency virus (HIV); and
the human manifests symptoms of the AIDS related complex or
acquired immunodeficiency syndrome. Alternatively, the mammal has a
disorder such as hypoxia, ischemia, hypoglycemia, trauma, seizures
or stroke, or is likely to become subject to these, i.e., could be
treated prophylactically.
By "NMDA receptor-mediated neuronal damage" is meant any neuronal
injury which results from stimulation or costimulation of the NMDA
receptor-channel complex, a receptor-channel complex which is found
on a subset of mammalian neurons and which includes a molecule that
interacts with NMDA or similar agonists (see below) to induce
neuron excitation.
By a "nitric oxide-generating compound" is meant any compound which
produces a sufficient amount of nitric oxide upon administration to
a mammal to reduce neuronal damage or injury.
Useful compounds of the second aspect of the instant invention
include any nitric oxide-generating compounds. Verification that a
particular compound provides protective oxidation of the NMDA
receptor itself is step well understood by those skilled in the art
(see, e.g., PCT WO 91/02810). Moreover, applicant notes that the
literature describes the enzyme, NO synthase, which produces nitric
oxide in certain cell types; this enzyme and its role in neuronal
function is discussed in, e.g., Garthwaite et al. (Trends in
Neurosciences 14:60, 1991) and Hope et al. (Proc. Natl. Acad. Sci.
USA 88:2811, 1991).
The two preferred compounds of the first aspect of the invention
(i.e., nitroglycerin and nitroprusside) provide the advantage of a
proven record of safe human administration (i.e., for treatment for
cardiovascular disorders).
Disorders which may be treated by the method of the invention
include hypoxia, ischemia, hypoglycemia, trauma, seizures, stroke,
AIDS dementia and other neurological manifestations of HIV (see,
e.g., U.S. Ser. No. 571,949) or other viruses affecting the nervous
system, and, generally, acute and chronic neurodegenerative
disorders, including, but not limited to Parkinson's disease,
Alzheimer's disease, and Huntington's disease .
Regarding compounds according to the second aspect of the
invention, the ability of NO to be transported and to cross cell
membranes facilitates therapies according to the invention.
Other features and advantages of the invention will be apparent
from the following detailed description and from the claims.
DETAILED DESCRIPTION
The drawings are first briefly described.
DRAWINGS
FIG. 1 is a bar graph showing that nitroprusside prevents
NMDA-mediated neurotoxicity.
FIG. 2 is a bar graph of intracellular Ca.sup.2+ concentration
(i.e., [Ca.sup.2+ ]i) in (a) control cells and in the presence of
(b) NMDA alone, (c) NMDA after dithiothreitol (DTT), and (d) NMDA
after DTT and nitroprusside.
The present invention is based on the finding that the compounds
nitroprusside and nitroglycerin reduce NMDA receptor
complex-mediated neuronal damage (see below). This reduction in
damage may be due to oxidation of the NMDA receptor at the redox
modulatory site. The reduction is associated with a decrease in
NMDA receptor-operated channel activation by excitatory amino acids
(such as NMDA) and a concomitant decrease in intracellular calcium
leading to neurotoxicity.
An increased level of one or more glutamate-related compounds is
associated with many neurodegenerative disorders (e.g., those
listed above). In addition to glutamate itself, neuronal injury may
result from stimulation of the NMDA receptor-channel complex by
other excitatory amino acids, such as aspartate, quinolinate,
homocysteic acid, cysteine sulphinic acid, or cysteic acid, or from
stimulation by excitatory peptides, such as N-acetyl aspartyl
glutamate.
Nitroglycerin (1,2,3-propanetriol trinitrate or glyceryl trinitrate
or GTN), nitroprusside and NO-generating derivatives of either one
of those compounds are considered to be particularly useful in the
invention.
Compounds of the second aspect of the invention (i.e., nitric
oxide-generating compounds and their derivatives) may be tested for
efficacy in reducing neuronal damage using the assays described
below--i.e. in assays of NMDA evoked ionic current (see, e.g., PCT
WO 91/02810), in assays of NMDA-evoked increases in intracellular
Ca.sup.2+ (see below), or in assays of neuronal cell death (see
below). An effective compound will cause a decrease in ionic
current, intracellular Ca.sup.2+ concentration, or in neuronal cell
death, respectively. Compounds most preferred in the invention are
those which effect the greatest protection of neurons from NMDA
receptor complex-mediated injury e.g., that injury resulting from
stimulation of the NMDA receptor by NMDA(as shown below) or other
excitatory amino acids or stimulation by excitatory peptides, such
as N-acetyl aspartyl glutamate.
ASSAY FOR NEURONAL CELL FUNCTION AND DEATH
To test compounds for their ability to prevent neurotoxicity,
neuronal cell death may be assayed as follows. Neonatal cortical
neurons were prepared according to the general method of Snodgrass
et al. (1980) Brain Res. 190:123-138; and Rosenberg et al (1988) J.
Neurosci. 8:2887-2899. Cultures are monitored following a brief
exposure (5 minutes) to 100 .mu.M NMDA, or to 5 mM DTT (for 5
minutes) followed by 100 .mu.M NMDA (for 5 additional minutes), and
overnight incubation (i.e., 16 to 24 hours). Experiments in vivo
suggest that a transient reducing state exists in the brain
following stroke; the introduction of the chemical reducing agent
DTT may mimic this reducing environment, increasing the similarity
of the in vitro assay to the in vivo situation. The candidate
compound is tested by addition (e.g., in a series of concentrations
ranging from 0.1 nM-10 mM) after DTT treatment but before NMDA
treatment. Incubations last 16-24 h at 37.degree. C. in an
atmosphere of 5 % CO.sub.2 /95% air. Neuronal cultures are scored
for cell survival after overnight incubation because NMDA toxicity
is often delayed by several hours following NMDA exposure. The
ability of cortical neurons to maintain phase-bright appearance and
exclude trypan blue is used as an index of survival (Rosenberg et
al., Neurosci. Lett. 103: 162-168, 1989).
A compound may be tested for utility in the method of the invention
using any type of neuronal cell from the central nervous system, as
long as the cell can be isolated intact by conventional techniques.
Although cortical neuron cultures are used above, retinal ganglion
cell neurons, spinal cord neurons, cerebellar granular neurons, or
any neuron containing NMDA receptors (e.g., neurons from other
regions of the cortex) may also be used. Such neurons may be
prenatal or postnatal.
There now follows an example of a compound useful in the method of
the invention and an illustration of its efficacy in reducing
neuronal damage. This example is provided to illustrate the
invention and should not be construed as limiting.
NITROPRUSSIDE PREVENTS NMDA RECEPTOR-MEDIATED NEUROTOXICITY
Using the assay described above, the compound nitroprusside was
tested for its ability to increase survival of neonatal cortical
neurons. The neuronal cells were incubated for 16-24 hours at
37.degree. C. in a humidified atmosphere of 5% CO.sub.2 and 95%
air.
As shown in FIG. 1, brief treatment (5 minutes) with NMDA (100
.mu.M) produced significant neuronal cell neurotoxicity (P
<0.01, indicated by an asterisk) after overnight incubation
[compare FIG. 1, column 1 (untreated control neurons) and column 2
(neurons treated with NMDA)]. A 5 minute exposure to 0.5 mM DTT
(prior to the brief treatment with NMDA) further increased
neurotoxicity [compare FIG. 1, column 2 (neurons treated with NMDA)
with column 3 (neurons treated with DTT followed by NMDA)]. In
additional cultures, nitroprusside was added for 5 minutes (after
DTT exposure but prior to NMDA treatment) to the growth media to a
final concentration of 1 .mu.M-1 mM. Nitroprusside prevented
neuronal cell death resulting from the combination of NMDA and DTT
[compare FIG. 1, column 3 (neurons treated with DTT followed by
NMDA) with column 4 (neurons treated with DTT followed by
nitroprusside followed by NMDA)]. Increased neuronal survival at 1
mM nitroprusside (FIG. 1, column 4) reached statistical
significance compared to the control (FIG. 1, column 1). An
analysis of variance was used to test for significance; this
analysis was followed by a Sheffe test for multiple comparison of
means (Hahn et al., 1988, supra). Doses of nitroprusside as low as
0.1 nM are expected to have neuroprotective effects.
MEASUREMENT OF INTRACELLULAR CA.sup.2+
The concentration of intracellular free Ca.sup.2+ ([Ca.sup.2+ ]i)
is measured in neonatal cortical neurons by digital imaging
microscopy with the Ca.sup.2+ sensitive fluorescent dye fura 2 as
follows. The same cortical neuronal cultures as described above are
used. During Ca.sup.2+ measurements, unless otherwise stated the
fluid bathing the neurons consists of Hanks' balanced salts: 137.6
mM NaCl, 1 mM NaHCO.sub.3, 0.34 mM Na.sub.2 HPO.sub.4, 0.44 mM
KH.sub.2 PO.sub.4, 5.36 mM KCl, 1.25 mM CaCl.sub.2, 0.5 mM
MgSO.sub.4, 0.5 mM MgCl.sub.2, 5 mM Hepes NaOH, 22.2 mM glucose,
and phenol red indicator (0.001% v/v); pH 7.2. NMDA and other
substances are usually applied to the neurons by pressure ejection
after dilution in this bath solution. Neuronal [Ca.sup.2+ ]i is
analyzed with fura 2-acetoxy-methyl ester (AM) as described
[Grynkiewicz, et al., J. Biol. Chem. 260:3440 (1985); Williams et
al., Nature 318:558 (1985); Connor et al., J. Neurosci. 7:1384
(1987); Connor et al., Science 240:649 (1988); Cohan et al., J.
Neurosci. 7:3588 (1987); Mattson, et al., ibid, 9:3728 (1989)].
After adding Eagle's minimum essential medium containing 10 .mu.M
fura 2-AM to the neurons, the cultures are incubated at 37.degree.
C. in a 5% CO.sub.2 /95% air humidified chamber and then rinsed.
The dye is loaded, trapped, and deesterified within 1 hour, as
determined by stable fluorescence ratios and the effect of the
Ca.sup.2+ ionophore ionomycin on [Ca.sup.2+ ]i is measured. During
Ca.sup.2+ imaging, the cells are incubated in a solution of
Hepes-buffered saline with Hanks' balanced salts. The [Ca.sup.2+ ]i
is calculated from ratio images that are obtained by measuring the
fluorescence at 500 nm that is excited by 350 and 380 nm light with
a DAGE MTI 66 SIT or QUANTEX QX-100 Intensified CCD camera mounted
on a Zeiss Axiovert 35 microscope. Exposure time for each picture
is 500 ms. Analysis is performed with a Quantex (Sunnyvale, Calif.)
QX7-210 image-processing system. Since cells are exposed to
ultraviolet light only during data collection (generally less than
a total of 20 s per cell), bleaching of fura 2 is minimal.
NITROPRUSSIDE DECREASES THE NMDA-MEDIATED INCREASE IN THE
INTRACELLULAR CONCENTRATION OF CA.sup.2+
NMDA-receptor mediated neurotoxicity has been shown to involve an
increase in intracellular Ca.sup.2+ concentration. The increase in
[Ca.sup.2+ ]i was documented in the following experiment.
Intracellular Ca.sup.2+ was measured as described above.
Application of 10 .mu.M NMDA produced a striking increase in
[Ca.sup.2+ ]i [FIG. 2, columns 2-5(b)]. Compared to control levels
[Ca.sup.2+ =50 nM Col. 1(a)]obtained before the addition of NMDA,
levels following NMDA addition increased to 200 nM. These results
represent the average [Ca.sup.2+ ]i measurement of six independent
neurons measured every two minutes for four trials. Using the same
neurons, the [Ca.sup.2+ ]i was allowed to return to the control
level, and the cultures were treated first with 5 mM DTT for 5
minutes (and washed out) and then 1O .mu.M NMDA was applied
repeatedly. This combined DTT and NMDA treatment produced an
increase in [Ca.sup.2+ ]i levels which was even greater than that
observed for NMDA treatment alone; specifically, an average level
of 400 nM free calcium ion concentration was measured. These
results are shown in columns 6-8 (c) and represent the average
measurement for the same six neurons measured every two minutes for
three trials. Calcium levels were again allowed to return to
control levels and the effect of nitroprusside on [Ca.sup.2+ ]i was
tested in the same neurons whose NMDA receptors had been previously
chemically reduced with 5 mM DTT. Following treatment with 5 mM
nitroprusside for 5 minutes (and wash out), 10 .mu.M NMDA did not
evoke as great a Ca.sup.2+ response. Indeed, the free calcium ion
concentration was very similar to that observed in control cultures
(approximately 50 nM averaged for the three trials at two minute
intervals for the same six neurons). These results are shown in
columns 9-11 (d).
Verification that the effect at issue involves the NMDA redox site
can be provided as follows.
Maximal chemical reduction of the site by 0.5-5 mM dithiothreitol
(DTT) prior to nitroprusside treatment increases NMDA responses
(i.e., NMDA produces an increased intracellular calcium
concentration (in part via ionic current) and neuronal death), but
nitroprusside (0.3-5 mM) prevents these effects. Pretreatment with
a strong oxidizing agent 5-5-dithio-bis-2-nitrobenzoic acid (DTNB,
0.1-2 mM, administered in a parallel experiment in place of DTT)
blocks the effect of nitroprusside on NMDA evoked maximum
[Ca.sup.2+ ]i increase and ionic current increase, although NMDA
itself still maintains some effect. In other words, a maximal
chemical oxidation with DTNB abrogates the effect of nitroprusside,
strongly suggesting that nitroprusside is acting in the same manner
under these conditions (i.e., as an oxidizing agent) because it has
no further effect after DTNB oxidation of the redox modulatory site
of the NMDA receptor-channel complex. It should be noted that once
the redox modulatory site is oxidized or reduced, even after
subsequent wash out of the redox agent, the site remains in this
state until another effective redox agent is introduced.
THERAPY
To prevent neuronal damage, compounds of the invention may be
administered by any of a number of routes in an amount sufficient
to attenuate an NMDA-evoked ionic current or a rise in [Ca.sup.2+
]i, or neurotoxicity. The compound may be included in a
pharmaceutical preparation, using a pharmaceutical carrier (e.g.,
physiological saline); the exact formulation of the therapeutic
mixture depends upon the route of administration. Preferably, the
compound is administered orally or intravenously, but it may also
be administered sublingually, by spray, by transdermal patch, or by
ointment. The preferred compounds, nitroglycerine or their
derivatives (including all those preparations commercially
available, e.g., those listed in the Physician's Desk Reference
(1991) under coronary vasodilators or under nitroglycerin or
nitroglycerin intravenous and including isosorbide mononitrate,
isosorbide dinitrate, nitroglycerin sublingual, NT-1, Niotrocor,
Nitroderm, Nitrodisc, Nitro-dur, Nitro-Dur II, Nitrofilm,
Nitrogard, Nitroglin, Nitropen, Tridil, and
6-chloro-2-pyridylmethyl nitrate) are administered at 0.01-1000
mg/day, in divided doses. Sodium nitroprusside--Na.sub.2
[Fe(CN).sub.5 NO]-2H.sub.2 O (from Elkins-Sinn, Inc., Cherry Hill,
N.J.) or Nipride (from Roche, Nutley, N.J.)--are administered
intravenously at 0.5-10 .mu.g/min. Other nitric oxide-generating
compounds, determined to be an effective neuroprotective agent by
the assays described herein, is administered orally, intravenously,
sublingually, by spray, or by transdermal patch or ointment at a
dosage suitable to reduce neuronal damage, or NMDA evoked ionic
current or increased [Ca.sup.2+ ]i. Generally, such compounds are
administered in dosages of 0.1-5 mg/day in divided doses. Treatment
may be repeated as necessary to prevent or alleviate neurological
injury. The compounds of the invention can be utilized to protect
against a number of neurotoxic disorders caused by elevated levels
of glutamate or related compounds. Such neurotoxic disorders
include ischemia, hypoxia, hypoglycemia, trauma, epilepsy,
Huntington's disease, and Alzheimer's disease and other
neurodegenerative disorders. The method of the invention is
particularly preferred for the treatment of AIDS dementia and other
neurological manifestations of the AIDS virus. The method may also
be used for reduction of neuronal damage resulting from infection
with other viruses which cause damage to the nervous system.
OTHER EMBODIMENTS
The method described herein is useful for reducing neuronal injury
in any mammal having NMDA receptors. Treatment of neuronal damage
in humans is the preferred utility; but the method may also be
employed successfully for veterinary purposes.
* * * * *