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Principal Investigator: Timothy C Cope
Organization: GEORGIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $462,934
Funding agency: National Cancer Institute
Abstract
The toxic effects of platinum-based compounds (PBCs) commonly used in chemotherapy weigh against their
usefulness as the major option for successfully combating lethal cancers. The decision to opt for survival
leaves people worldwide to suffer with PBC neurotoxicity that reduces quality of life by causing neurological
disorders both during and long after treatment. Pain, strange sensations, fatigue, and difficulty with balance
and walking are common symptoms, collectively known as chemotherapy-induced neuropathy (CIN). During
treatment, both sensory and motor neurons are observed to fire unintentionally, i.e. they exhibit spontaneous
firing (SA), and evidence suggests that SA bears responsibility for the earliest signs of distress, including
uncontrolled muscle contraction, cramping, and unusual body sensations. Prolonged impact of SA is
suggested by observations that the intensity of acute signs and symptoms of toxicity is predictive of the
severity of symptoms that develop after with PBC accumulation and persist for months or years after treatment.
This situation describes the urgent need for prevention or treatment of PBC effects on abnormal neuronal
activity and its underlying causes, but no effective solution has been found. The research project proposed
here is designed to meet this need by examining the effects of human-scaled doses of PBC on motor neurons
in cancer-bearing rats studied in vivo. The proposal prioritizes three specific aims as the most logical and
impactful next steps, all supported and proven feasible by preliminary experiments and findings. Aim 1 will test
whether PBC accumulation in motor neuron cell bodies within the central nervous system (CNS) is necessary
or sufficient to induce SA. Emphasis on the CNS is a new direction in the field that breaks with common, yet
untested consensus that SA originates at unusual, i.e. ectopic sites of firing out in the peripheral nervous
system. This new direction is driven by recent and conclusive findings presented here that SA in motor
neurons is produced within the CNS. A possible cause of SA will be tested using methods to measure and
manipulate PBC accumulation in motoneurons. Aim 2 will take advantage of the exceptional access of spinal
motor neurons for studying, within a living animal, the biophysical mechanisms underlying changes in neuronal
excitability and SA. The results will provide the first ever detail about the effects of PBC on intrinsic excitability
of motor neurons and will guide understanding of effects that are entirely unknown for other neurons in the
CNS. Aim 3 will test the possibility that SA in motor neurons is driven synaptically by SA shown here for
sensory neurons. This systematic examination of SA induced by PBC neurotoxicity will significantly advance
the field by critically assessing three major candidate mechanisms having strong potential for evidence-based
impact on urgently needed development of preventative measures or treatments.
Terms: <1-OHP><Action Potentials><Acute><Afferent Neurons><After Care><After-Treatment><Aftercare><Animals><Axon><Biophysical Process><Biophysics><Blood - brain barrier anatomy><Blood-Brain Barrier><CDDP><CNS Nervous System><Cancer Survivor><Cancers><Central Nervous System><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Chronic><Cimetidine><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clampings><Clinical><Clinical Trials><Closure by clamp><Combination Chemotherapy Regimen><Common Rat Strains><Consensus><Cramp><Cysplatyna><Data><Development><Diagnostic Findings><Dichlorodiammineplatinum><Distress><Dorsal Root Ganglia><Dorsal Roots><Dose><Dysesthesias><Dysfunction><Dyskinesia Syndromes><Electrophysiology><Electrophysiology (science)><Equilibrium><Esthesia><Exclusion><Exhibits><Fasciculation><Fatigue><Fire - disasters><Fires><Functional disorder><Hemato-Encephalic Barrier><Human><Hyperkinesia><Hyperkinesis><Hyperkinetic Movements><Infiltration><Ion Channel><Ionic Channels><Knowledge><Lack of Energy><Lidocaine><Life><Lignocaine><Long term disability><Malignant Neoplasms><Malignant Tumor><Measures><Membrane Channels><Methods><Modeling><Modern Man><Motor Cell><Motor Neurons><Movement Disorder Syndromes><Movement Disorders><Muscle><Muscle Cell Contraction><Muscle Contraction><Muscle Cramp><Muscle Spasm><Muscle Tissue><Muscle fasciculation><Muscular Contraction><Muscular Cramp><Muscular Fasciculation><Muscular Spasm><N-Cyano-N'-methyl-N''-(2-(((5-methyl-1H-imidazol-4-yl)methyl)thio)ethyl)guanidine><Nerve Cells><Nerve Unit><Nervous System><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Fasciculation><Neuraxis><Neurocyte><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurological Disorders><Neurons><Neurophysiology / Electrophysiology><Outcome><Pain><Painful><Patients><Peripheral><Peripheral Nervous System><Persons><Peyrone's Chloride><Peyrone's Salt><Physiopathology><Platinum><Platinum Black><Platinum Diamminodichloride><Preventative measure><Preventative treatment><Prevention><Preventive measure><Preventive treatment><Property><Pt element><QOL><Quality of life><Quimioterapia><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Research Grants><Research Project Grants><Research Projects><Sensation><Sensory><Sensory Neurons><Severities><Signs and Symptoms><Site><Spasm><Spinal><Spinal Ganglia><Symptoms><Synapses><Synaptic><Testing><Thinking><Toxic effect><Toxicities><Voltage-Clamp Technics><Voltage-Clamp Technique><Walking><acute symptom><balance><balance function><biophysical analysis><biophysical foundation><biophysical mechanism><biophysical principles><biophysical sciences><biophysical studies><bloodbrain barrier><bodily sensation><cancer chemotherapy><channel blockers><chemotherapy><chemotherapy induced neuropathy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><common symptom><design><designing><developmental><dorsal root ganglion><electrophysiological><evidence base><experiment><experimental research><experimental study><experiments><extracellular><fire><immunoreactivity><in vivo><inhibitor><malignancy><meeting><meetings><motoneuron><muscular><neoplasm/cancer><neural><neural cell body><neurological disease><neuron toxicity><neuronal><neuronal cell body><neuronal excitability><neuronal toxicity><neurotoxic><neurotoxicity><novel><oxaliplatin><oxaliplatine><pathophysiology><post treatment><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><response><soma><somatosensory><spinal nerve posterior root><success><symptom treatment><symptomatic treatment><synapse><thoughts><treat symptom><treatment effect>