Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders

Abstract

Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer’s disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…For example, unhealthy diet and exercise may have different impacts on individuals and require different treatment strategies than those individuals predisposed to genetically inherited familial diseases [8]. Sex, genetic risks, and age are important variables that should be considered during the development stage for AD therapeutics [9,10]. The dosing regimen, formulation, and the route of administration all have significant effects on clinical success [10].…”

“…Sex, genetic risks, and age are important variables that should be considered during the development stage for AD therapeutics [9,10]. The dosing regimen, formulation, and the route of administration all have significant effects on clinical success [10]. Past approaches targeting moderate and severe AD pathology have had minimal success, in part because of the single target strategy for a multifactorial pathology.…”

The Impact of Gonadal Hormones on the Expression of Human Neurological Disorders

“…By impacting GABAergic and glutamatergic pathways, allopregnanolone and THDOC elicit sedative-hypnotic, anticonvulsant and anxiolytic effects relevant to the pathophysiology of epilepsy (see the section Reproductive Hormones and Epilepsy) and various mood disorders. On the other hand, the net excitatory influences of pregnanolone sulfate and dehydroepiandrosterone sulfate may bolster memory functions compromised by Alzheimer disease and related dementias (section Reproductive Hormones and Alzheimer Disease) and exacerbate anxiety disorders [5,6,8]. …”

“…But whether the estrogenic influences on dopaminergic neurotransmission in this disease are predominantly stimulatory or inhibitory remains uncertain [2]. In animal models of Parkinson disease, the neurosteroid allopregnanolone enhances neurogenesis in the substantia nigra, modulates dopamine release and improves motor control [8]. The latter findings may have clinical significance given that allopregnanolone concentrations are reportedly low in the plasma and cerebrospinal fluid of patients with idiopathic Parkinson disease [50,51].…”

“…In light of the data reviewed in the preceding section, Irwin et al [8] have advocated clinical trials to investigate the potential neuroprotective and therapeutic benefits of allopregnanolone in subjects with Parkinson disease.…”