Use of carbon monoxide dependent guanylyl cyclase modifiers...

Details Use of carbon monoxide dependent guanylyl cyclase modifiers... Use of carbon monoxide dependent guanylyl cyclase modifiers...

1999-10-19

2002-01-15

Park, Hankyel T. (Department: 1671)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S007210, C514S045000, C514S310000, C514S262100, C544S265000, C544S276000

Reexamination Certificate

active

06338963

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates in general to the control of neural activity and to the treatment of neural disorders. More particularly, the present invention is directed to methods for the modification of mammalian neural activity through the administration of carbon monoxide dependent guanylyl cyclase modulating purine derivatives which selectively and controllably induce the in vivo genetic expression of naturally occurring genetically encoded molecules including neurotrophic factors. The methods of the present invention may be used to affect a variety of neurological activities and to therapeutically or prophylactically treat a wide variety of neurodegenerative and neurological disorders.
BACKGROUND OF THE INVENTION
The evolution of the central nervous system in mammals was a natural response to an increasingly complex environment requiring solutions to difficult problems. The resulting structure is an intricate biochemical matrix that is precisely controlled and attenuated to an elaborate system of chemically modulated regulatory pathways. Through an elaborate series of highly specific chemical reactions, these pathways oversee and direct every structural and operational aspect of the central nervous system and, through it, the organism itself. Normally, the complex interplay of the various control systems cooperates to produce a highly efficient, versatile central nervous system managed by the brain. Unfortunately, when the biochemical matrix of the central nervous system is damaged, either through age, disease, or other reasons, the normal regulatory pathways may be incapable of effectively compensating for the loss. In such cases, it would be highly desirable to modify or supplement the neural mechanisms to prevent such disorders or compensate for them. That is the focus of the present invention.
More specifically, the mammalian brain is composed of approximately 10 billion nerve cells or neurons surrounded by an even greater number of support cells known as neuroglia or astrocyte cells. Neurons, like other cells of the body, are composed of a nucleus, a cytoplasm, and a surrounding cell membrane. However, unlike other cells, neurons also possess unique, fiber-like extensions allowing each individual nerve cell to be networked with literally thousands of other nerve cells to establish a neural infrastructure or network. Communication within this intricate network provides the basis for all mental processes undertaken by an organism.
In each nerve cell, incoming signals are received by neural extensions known as dendrites which may number several thousand per nerve cell. Similarly, neural information is projected along nerve cell axons which may branch into as many as 10,000 different nerve endings. Together, these nerve cell axons and dendrites are generally termed neurites through which each individual neuron can form a multitude of connections with other neurons. As a result, the number of possible neural connections in a healthy brain is in the trillions, giving rise to tremendous mental capacity. Conversely, when the connections within the neural network break down as nerve cells die or degenerate due to age, disease, or direct physical insult, the mental capacity of the organism can be severely compromised.
The connection of the individual axons with the dendrites or cell bodies of other neurons takes place at junctions or sites known as synapses. It is at the synapse that the individual neurons communicate with each other through the flow of chemical messengers across the synaptic junction. The majority of these chemical messengers, or neurotransmitters, are small peptides, catecholamines, or amino acids. When the appropriate stimulus is received by a neural axon connection, the neurotransmitters diffuse across the synapse to the adjacent neuron, thereby conveying the stimulus to the next neuron across the neural network. Based on the complexity of the information transferred between the nerve cells, it is currently believed that between 50 and 100 distinct neurotransmitters are used to transmit signals in the mammalian brain.
Quite recently, it was discovered that nitric oxide (NO) and carbon monoxide (CO) may function as neurotransmitters. These gaseous molecules appear to participate in a number of neuronal regulatory pathways affecting cell growth and interactions. In the brain, as well as in other parts of the body, CO is produced by the enzyme heme oxygenase II (HO). Whether produced from the HO enzyme or from other sources, it is believed that when CO diffuses into a neuron it induces a rise in a secondary transmitter molecule known as cyclic guanosine monophosphate (cGMP) by modulating an enzyme known as guanylate cyclase or guanylyl cyclase. Thus, CO acts as a signaling molecule in the guanylyl cyclase regulatory pathway. The resultant increase in cGMP levels appears to modify several neurotrophic factors as well as other neuronal factors which may induce, promote, or modify a variety of cellular functions including cell growth and intercellular communication.
Neurotrophic factors are molecules that exert a variety of action stimulating both the development and differentiation of neurons and the maintenance of cellular integrity and are required for the survival and development of neurons throughout the organism's life cycle. Generally, neurotrophic factors may be divided into two broad classes: neurotrophins and pleiotrophins. Pleiotrophins differ from the neurotrophins in that they lack a molecular signal sequence characteristic of molecules that are secreted from cells and in that they also affect many types of cells including neurons. Two effects of neurotrophic factors are particularly important: (i) the prevention of neuronal death and (ii) the stimulation of the outgrowth of neurites (either nascent axons or dendrites). In addition, it appears that CO-induced neurotrophic factors may reduce the membrane potential of nerve cells making it easier for the neurons to receive and transmit signals.
Many of today's researchers believe that memory is associated with the modification of synaptic activity, wherein the synaptic connections between particular groups of brain neurons become strengthened or facilitated after repeated activation. As a result, these modified connections activate much more easily. This type of facilitation is believed to occur throughout the brain but may be particularly prominent in the hippocampus, a brain region which is critical for memory. The stimulation of neuronal pathways within the hippocampus can produce enhanced synaptic transmission through these pathways for many days following the original stimulation. This process is known as long term potentiation.
More particularly, long term potentiation is a form of activity-dependent synaptic electrical activity that is exhibited by many neuronal pathways. In this state, generally accepted as a type of cellular memory, nerve cells are more responsive to stimulation. Accordingly, it is widely believed that LTP provides an excellent model for understanding the cellular and molecular basis of synaptic plasticity of the type that underlies learning and memory in vertebrates, including man.
NO and CO are currently the leading candidates for messenger substances that facilitate LTP because inhibitors of these compounds retard the induction of potentiation. The ability to modify neural activity and to increase the ease of LTP using these or other signal transducers could potentially increase learning rates and cognitive powers, possibly, compensating for decreased mental acuity. Prior to the present invention, there were no known agents which could operate on the cellular level in vivo to reliably modify neural regulatory pathways so as to facilitate the LTP of neurons.
In contrast to the enhanced mental capacity provided by long-term potentiation, mental functions may be impeded to varying degrees when the neuronal network is disrupted through the death or dysfunction of constituent nerve cells. While the decline in mental abilities is directly relat

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