Target Identification and Drug Discovery

Tracing the sequence of molecular event responsible for a cognitive function such as memory is a step-by-step process.  Each molecular event regulates and can be regulated by the next event to ultimately determine strength of a synaptic connection, the structure of that connection and the coordinated function of the connection in concert with other synaptic connections.  Assemblies of neurons and the synaptic connections among them become “networks” that regulate diverse functions of the brain such as attention, emotion, movements, memory and even decision-making.

To conclusively determine how networks regulate cognitive functions such as memory, a number of criteria must be satisfied. These include:

• Correlation – the molecular event must change in a manner that is closely correlated with the learning and memory task involved.
• Synaptic – Neuronal Regulation – the molecular event or events must regulate the underlying synaptic and neuronal signaling necessary for the memory process.
• Causal Role – the molecular events must be necessary and sufficient for the memory process to occur.
• Predictive Pharmacology – drugs that target the molecular event should have predictable facilitating or blocking effects on the memory process.

By following basic research on the molecular events of memory and satisfying such criteria as above, BRNI scientists have identified key molecules in the various stages of memory formation.  PKC epsilon, for example, was found to be for inducing the required synaptic macroscopic and microscopic structures for memory storage.  Similarly, carbonic anhydrase and its regulation of the inhibitory synapses called GABAergic synapses was found to be critically involved in the process of attention that precedes the learning and memory of a particular task.

Bryostatin

Blanchette Rockefeller Neurosciences Institute (BRNI) has discovered that a cancer drug – Bryostatin – enhances the formation of new connections in rat brains during memory storage.  This drug could potentially increase normal memory capacity in humans as well as repair and restore memory lost from Alzheimer’s disease (AD), stroke and head trauma.

BRNI research shows that a healthy brain normally undergoes some ‘rewiring’ when it stores memories.  Bryostatin enhances this rewiring in normal healthy brains and also creates new connections in brains that have been ravaged by Alzheimer’s disease, stroke or head trauma.

BRNI Scientific Director Daniel Alkon, M.D. and Jarin Hongpaisan, Ph.D. used high-powered electron microscopes to directly visualize these synaptic connections between neurons. They also used molecular markers to label these connections to confirm the synaptogenesis induced by memory and Bryostatin.

In previous BRNI studies, Bryostatin was found to markedly increase survival of mice with human Alzheimer's genes, decrease the production of the toxic Alzheimer's protein called A Beta, and increase the production of the healthy proteins from human cells.
Bryostatin also shows the ability to accelerate the production of synapses when paired with learning exercises. According to Dr. Alkon, this could eventually lead to new treatment therapies for children with compromised memory activity.

In 2004, BRNI received patent protection for the use of Bryostatin - originally developed as a cancer drug - to treat Alzheimer's disease. BRNI is preparing now for the first clinical trials of Bryostatin for the treatment of neurological disorders. Clinical trials will test whether Bryostatin’s promising preclinical results generalize to humans.  Now BRNI scientists are synthesizing new chemical compounds to accomplish molecular, synaptic, and cognitive consequences that are similar to those of Bryostatin but with greater specificity, using only one particular form of PKC known as PKC epsilon.

Carbonic Anhydrase Activators

Other drugs developed by BRNI scientists are based on targets identified within the memory and Alzheimer's disease molecular pathways.  These include the carbonic anhydrase activators for enhancing attention that target GABA ergic synaptic transmission.  This new class of drugs is being developed to treat attention deficit disorder as well as to enhance attention-gated learning.  Blocking of carbonic anhydrase may be useful for the treatment of Post-Traumatic Stress Disorder for which it may be important to minimize the contexts to which a particular traumatic event has been generalized.  Our scientists discovered these new drug modalities by first identifying critical molecular steps involved in brain functions such as attention and attention-gated learning and memory.  One such step involves an enzyme called carbonic anhydrase that regulates the flow of ions through membrane channels to cause inhibition at GABA ergic synapses in the brain.  Many years ago carbonic anhydrase regulation by phenylalanine was implicated in a genetic disease that causes mental retardation.  This disease, phenylketonuria, involves a class of molecules, phenylalanine compounds, that is now being developed at BRNI to enhance learning as well as to treat attention deficit disorder.