Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-07
2003-04-22
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06552053
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods for modulating attention, learning, and memory by controlling carbonic anhydrase activity. More particularly, the invention involves administering a compound that alters carbonic anhydrase activity in the brain thereby affecting establishment of a theta rhythm in the brain.
Acetazolamide is a generic drug manufactured in forms of capsule, tablets or injectable preparations. Inhibition of carbonic anhydrase activity by acetazolamide is a therapeutic approach in use or suggested for several indications, including glaucoma, conjunctive heart failure, mountain sickness, sleep apnea and petit mal seizures (epilepsy), and body fluid retention. These therapeutic avenues are diverse and none of them suggests any cognitive impacts of regulating carbonic anhydrase activity.
Hippocampal theta (&thgr;) rhythm (synchronized neuronal discharge) is believed to play a critical role in information processing and memory consolidation during exploratory behavior. Theta activity depends on cholinergic inputs and &thgr; discharges of GABAergic interneurons, and can be induced e.g. by a cholinergic receptor agonist (carbachol). GABA acts as an inhibitor of action potentials by keeping the GABA-Cl
−
channel open. This channel is an anion transporter, exchanging Cl
−
for HCO
3
−
. Maintaining the open channel allows Cl
−
to flow into the cell to hyperpolarize the membrane potential. Cholinergic components depolarize the membrane potential, and if threshold is reached an action potential is created. It is believed that the synchronized depolarization and excitation creates an oscillating membrane potential leading to &thgr; activity, but the mechanism has remained unknown. GABAergic depolarization can be induced by enhancing HCO
3
−
conductance through GABA
A
receptor-channels in adult hippocampal cells, a response sensitive to carbonic anhydrase inhibitors (Kaila '93). However, no association has previously been identified between carbonic anhydrase inhibition at the cellular-electrophysiological level on the one hand, and a reduction in theta rhythm on the other.
There have been few medications suitable for improving attention in those who need it, and no effective medications for those who need to suppress learning painful memories. There is a need to elucidate a simple biochemical target for controlling the extremely complicated brain-wide effect of theta rhythm, and the even more complex events leading to attention and learning. Such a target would be invaluable in identifying specific compounds for achieving the desired cognitive effects.
This invention differs from the prior art in modifications, which were not previously known or suggested, including the use of carbonic anhydrase regulators to alter theta rhythm and produce cognitive effects in mammals. The methods of the invention provide advantages that were not previously appreciated, such as the ability to selectively enhance attention and learning. This invention satisfies a long felt need for compounds that selectively enhance or inhibit attention and learning.
The widespread use of acetazolamide, with no substantial cognitive side effects reported, makes it surprising to discover that the compound does inhibit spatial learning in animals, and presumably in humans. This invention thus identifies a previously unrecognized problem, and shows how to solve it, e.g. by careful dosing regimens of acetazolamide so as to reduce its cognitive side effects.
SUMMARY OF THE INVENTION
Acetazolamide, a drug commonly used for glaucoma and diuresis, has been found to specifically block acquisition of new memories. Post-traumatic stress disorder involves learning new contexts for traumatic memories. These new contexts would be blocked during the administration of acetazolamide. Thus, acetazolamide can be used for short-term memory suppression, for example to prevent post traumatic stress syndrome during a period of trauma.
More generally, based on comprehensive electrophysiologic studies of GABAergic depolarization of CA1 hippocampal cells, we have implicated bicarbonate conductance enhancement as critical for theta rhythm and spatial maze learning. Bicarbonate-mediated GABAergic depolarization mediated by carbonic anhydrase (blocked by acetazolamide) is a target for drugs that either block or enhance new memory formation. Blocking drugs would have application in post-traumatic stress disorders and related diseases. Cognitive enhancing drugs would have wide application in the treatment of neurodegenerative disorders, especially those involving dementia.
Surprisingly, according to the invention, the GABAergic transformation is associated with establishment of a theta rhythm, and both phenomena can be controlled together by modifying neuronal carbonic anhydrase activity. Although it was previously thought that the transformation was related to attention, and that the theta rhythm was associated with attention, there was no teaching that the two were intimately connected and subject to common control via carbonic anhydrase inhibitors or activators.
The invention relates to a method for blocking associative memory acquisition comprising determining a need for blocking, and administering an inhibitor, such as acetazolamide, of carbonic anhydrase activity in the brain, thereby blocking the memory acquisition. The method can also be used for suppressing attention, learning and/or memory formation in a mammal comprising determining a need for suppressing, and administering an inhibitor of carbonic anhydrase activity in an amount effective to inhibit carbonic anhydrase activity in the brain, preferably in neurons. The inhibitor may be selected from the group consisting of acetazolamide, benzolamide, and analogs thereof. An analog is a molecule having a structure function relationship similar to the named compound that allows it to bind to and inhibit carbonic anhydrase in the brain. Although, the inhibitor prevents establishment of a theta rhythm during learning, it does not affect memory retrieval from formed memories, or sensory or locomotor behaviors.
In yet another aspect of the invention, the method can be used for improving attention and/or memory acquisition in a patient comprising determining the need for improved attention and/or memory acquisition, and administering to the patient a stimulator of intraneuronal carbonic anhydrase activity in an amount sufficient to stimulate intraneuronal carbonic anhydrase activity. The patient may be healthy, i.e. have no neurodegenerative disorder or the patient may suffer from a neurodegenerative disease. The invention may also be used for treating a neurodegenerative disorders comprising administering an effective amount of a stimulator of intraneuronal carbonic anhydrase activity. The cognitive ability may be enhanced. The neurodegenerative disease can also be dementia.
The invention further provides a method for modulating attentive cognition comprising administering a compound that alters intraneuronal carbonic anhydrase activity in an amount sufficient to affect the establishment of a theta rhythm. The theta rhythm can be affected by modulating bicarbonate-mediated GABAergic depolarization. Moreover, the attentive cognition may be selected from memory formation, learning, spatial memory, and attention. In one aspect the modulating is stimulating. The compound can be administered in an amount sufficient to inhibit intraneuronal carbonic anhydrase activity, establish of a theta rhythm, and suppress memory acquisition. The compound may also be administered in an amount that does not affect memory retrieval. Moreover, the suppression may occur about one half to one hour after administering the inhibitor compound.
The term “attentive cognition” is meant to encompass memory formation, learning, spatial memory, and attention. The inhibiting of carbonic anhydrase is preferably selective in that it reduces memory acquisition, but not memory retrieval.
In another aspect of the invention, the method may be used for modula
Alkon Daniel L.
Sun Miao-Kun
Zhao Wei-Qin
Gollin Michael A.
Jarvis William R. A.
The United States of America as represented by the Secretary of
Venable
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