Some of the earliest signs of neurodegeneration (anosmia, constipation, dysautonomia, sleep dysregulation), seen in Alzheimer’s, Parkinson’s and other diseases, as well as cognitive loss and depression in older adults, occur due to profound neuronal pathology in the locus coeruleus. This important brain stem nucleus is the origin of most ascending transmission of norepinephrine (also known as noradrenaline) that modulates and activates higher brain functions in limbic and cortical regions and supports cerebral homeostasis, through a pan-cerebral heterocellular action.
With LC decline in neurodegeneration, and to a lesser extent with age, the neuronal, metabolic and immunological support provided by norepinephrine, via many neural and glial cell types, begins to erode, causing a progressive and catastrophic neural decline, marked by neurotrophic collapse, inflammation, lysosomal suspension and atrophy. Over years, memory, cognitive and executive function deteriorate, often preceded by increasing dysfunction in sleep and autonomic control. Often, these degenerative characteristics are dominated by a patient’s loss of arousal, motivation and positive mood and progressive loss of autonomic reflexes – early indicators of LC decline.
CuraSen’s approach is focused on restoring the impact of noradrenergic stimulus by directly activating specific targets, with a focus on the β2 and α1A adrenoceptors, in the brain. Using our novel compounds, we anticipate restoring the function of multiple cell types in the brain that depend on norepinephrine, including neurons, astrocytes, microglia and cerebrovascular cells, to broadly improve cerebral integrity and function. Such an approach is anticipated to improve core cognitive functions, including arousal, executive function, memory and mood, and help restore normal daily functions, including blood pressure control, as well as reduce the neuroinflammatory and protein accumulations associated with the progression of disease. Ultimately, our goal is to reduce the life-altering symptoms of neuropsychiatric and neurodegenerative disease, and slow or reverse disease progression.
Our first-in-class compounds targeting β2 adrenoceptors have demonstrated proof-of-concept and safe delivery to the CNS of this key stimulus leading to important improvements in cognition and mood, in either Parkinson’s or Alzheimer’s patients.
Additionally, in neurogenic orthostatic hypotension, our best-in-class compound selectively targets α1A adrenoceptors in the periphery, to stably and safely control blood pressure and cerebral perfusion.