Development of Natural Product Compound Combinations for the Treatment of Neurological Disease States

Abstract

Due to increased advancements in the treatment of various disease conditions, the progression of our population towards improved lifespans along with an increased range of functional years is not surprising. Unfortunately, no therapeutic is available that can prevent or reverse the pathophysiological effects of age. Aging is marked by increased incidence of neurological disease states including both cerebrovascular (e.g., ischemic stroke (IS)) and neurodegenerative conditions (e.g., Alzheimer’s disease (AD)) and are known to be common causes of morbidity and mortality in the world. Drug development campaigns for IS and AD are complex and challenging when considered on their own, let alone in correlation to each other. A common correlation between these diseases can be found in the pathological overlap and involvement of the neurovascular unit (NVU). Indeed, all components of the NVU (i.e., glial cells, pericytes, endothelial cells, neurons, extracellular matrix (ECM)) participate in pathological processes associated with neurological disease states. Between oxidative stress, inflammation, increased glutamate concentrations (i.e., excitotoxicity) effects on the central nervous system (CNS) and blood-brain barrier (BBB) dysfunction, the impact of aging on the NVU is clearly visible in the pathology of cerebrovascular and neurodegenerative diseases. Furthering our scientific understanding means the consolidation of research following the etiology, pathophysiology, and current pharmaceutical landscape of therapeutics. Before the need for discovery of novel therapeutics and/or development of improved therapeutic strategies can be fulfilled, a deeper look into current behavioral paradigms must be covered. Translationally relevant research requires the use of robust behavioral studies aimed at identifying the correct pathological states, as well as providing a clinically relevant opportunity for observing drug treatment. In the context of neurological disease states, this includes evaluation of cognitive decline, such as that involved in spatial memory consolidation and recall. Many universally accepted paradigms rely on drivers and processes of memory consolidation that do not accurately reflect cognitive impairment and/or decline associated with neurological diseases. For example, behavioral assessment of spatial memory frequently involves eliciting the compartmentation of memory based on “fight or flight”. Although these methods are capable of statistically significant results, stress imposed on research animals used within these approaches limits the biological significance and translatability of preclinical behavioral results. Over the past several years, drug discovery efforts for AD therapeutics have been hampered by problems involving inadequate targeting of key drivers. AD therapeutics have primarily focused on removal of neuritic plaques, which are comprised of amyloid-beta (Aβ) protein and are associated with many adverse pathological states of AD (i.e., neuroinflammation, oxidative stress, and reactive astrogliosis and microgliosis). Agents such as the biologic Aβ targeting drugs aducanumab (Aduhelm™) and lecanemab-irmb (Legembi™) have received accelerated approval from the United States Food and Drug Administration (FDA) and yet have failed to prevent, or even slow, pathological cognitive AD progression in clinical trials. Given the overlap of AD and IS pathologies, a change in approach is required in the drug discovery process. AD and IS are highly complex disease states where multiple CNS cell types (i.e., neurons, astrocytes, microglia, endothelial cells, pericytes) participate in integrated pathological mechanisms that are influenced by genetic variability, sex differences, aging, and environmental factors. The consideration of overlapping pathologies (i.e., mitochondrial bioenergetics, oxidative stress, neuroinflammation, microglial phagocytosis, neurotransmitter homeostasis, blood-brain barrier integrity and neuronal death) between neurological disease states must be taken into account when considering potential therapeutics, and improvement of therapeutic combinations for targeting multiple aspects at once. In this dissertation, the utility of targeting multiple pathways associated with neurological disease states using combinations of natural product compounds was studied. Using a combination of in vitro and in vivo approaches, these natural product compounds were shown to have beneficial effects that may impact pharmacotherapy of neurological disease states including activation of mechanisms associated with neuronal repair and improvement of cognitive performance. Overall, these studies demonstrate the importance of targeting multiple cellular components of the NVU for development of novel treatment strategies for neurological disease states.