sodium-oxybate and Alzheimer-Disease

The high energy demands of the poorly myelinated long axon hippocampal and cortical neurons render these neurons selectively vulnerable to degeneration in Alzheimer's disease. However, pathology engages all of the major elements of the neurovascular unit of the mature Alzheimer brain, the neurons, glia and blood vessels. Neurons present with retrograde degeneration of the axodendritic tree, capillaries with string vessels and markedly reduced densities and glia with signs of inflammatory activation. The neurons, capillaries and astrocytes of the mature Alzheimer brain harbor structurally defective mitochondria. Clinically, reduced glucose utilization, decades before cognitive deterioration, betrays ongoing energy insufficiency. β-hydroxybutyrate and γ-hydroxybutyrate can both provide energy to the brain when glucose utilization is blocked. Early work in mouse models of Alzheimer's disease demonstrate their ability to reverse the pathological changes in the Alzheimer brain and initial clinical trials reveal their ability to improve cognition and every day function. Supplying the brain with energy holds great promise for delaying the onset of Alzheimer's disease and slowing its progress.

Topics: Alzheimer Disease; Animals; Brain; Humans; Neurons; Sodium Oxybate

We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis.

Topics: Alzheimer Disease; Animals; Butylene Glycols; Butyrates; gamma-Aminobutyric Acid; Humans; Hypoxia; Sodium Oxybate

Gamma-hydroxybutyrate (GHB or Xyrem(R)) is frequently used in humans for several clinical indications, including anesthesia, narcolepsy/cataplexy, and alcohol-withdrawal symptoms. Pharmacological effects induced in the brain by therapeutic doses of Xyrem(R) are generally GABAergic-dependent. These effects allow sedation, stress/anxiety reduction, deep sleep induction, decrease of neuroinflammation, and neuroprotection. Furthermore, Xyrem(R) promotes the expression of pivotal genes reducing toxic proteinopathies, as demonstrated in laboratory animal models. Altogether, these data represent additional evidence to suggest that Xyrem(R) may be tested during repeated short periods in populations at risk for Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Humans; Neuroprotective Agents; Sodium Oxybate

A reduction in cerebral glucose utilization is one of the earliest signs of Alzheimer's disease. Although the exact cause of this reduction is not known, gathering evidence suggests that it is part of a complex metabolic adaptation to oxidative stress during which glycolysis and oxidative phosphorylation are turned down, glucose metabolism is shifted to the pentose phosphate pathway to generate antioxidant reducing factors such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, and the gamma-aminobutyric acid (GABA) shunt is activated to provide glutamate as an alternate source of energy. In the face of these adaptive metabolic changes, the Alzheimer brain runs short of energy and begins to digest itself. The very early induction of macroautophagy attests to the search for nutrients. In clinical trials, antioxidants alone have not been effectively able to influence the course of the disease as these agents do not meet the energy and nutritional requirements of the brain. Evidence is presented that gammahydroxybutyrate, a natural product of the GABA shunt, can provide the necessary energy, carbon, and antioxidant power and that its use may be able to delay the onset and progress of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Brain; Energy Metabolism; Glucose; Humans; Oxidative Stress; Sodium Oxybate

Although the cause of Alzheimer's disease is unknown, oxidative stress, energy depletion, excitotoxicity and vascular endothelial pathology are all considered to play a part in its pathogenesis. In reaction to these adverse events, the Alzheimer brain appears to deploy a highly conserved biological response to tissue stress. Oxidative metabolism is turned down, the expression of antioxidative enzymes is increased and intermediary metabolism is shifted in the direction of the pentose phosphate shunt to promote reductive detoxification, repair and biosynthesis. Gathering evidence suggests that the release of beta-amyloid and the formation of neurofibrillary tangles, the two hallmarks of Alzheimer's disease, are components of this protective response. Gammahydroxybutyrate (GHB), an endogenous short chain fatty acid, may be able to buttress this response. GHB can reduce glucose utilization, shift intermediary metabolism in the direction the pentose phosphate shunt and generate NADPH, a key cofactor in the activity of many antioxidative and reductive enzymes. GHB has been shown to spare cerebral energy utilization, block excitotoxicity and maintain vascular integrity in the face of impaired perfusion. Most important, GHB has repeatedly been shown to prevent the tissue damaging effects of oxidative stress. It may therefore be possible to utilize GHB to strengthen the brain's innate defences against the pathological processes operating in the Alzheimer brain and, in this way, stem the advance of Alzheimer's disease.

Topics: Alzheimer Disease; Energy Metabolism; Humans; Oxidative Stress; Sodium Oxybate

Varying degrees of metabolic arrest are used by many living species to survive in a harsh environment. For example, in hibernating mammals, neuronal activity and cerebral metabolism are profoundly depressed in most regions of the brain and limited energy resources are deployed to maintain vital cell functions. Gathering evidence suggests that energy resources are also limited in both Alzheimer's and Parkinson's diseases, and that this promotes metabolic stress and the degenerative process. Key steps in this process are energy requiring, and this further compromises cell energy reserves. It may be possible to slow the progress of these diseases by inducing slow-wave sleep (SWS) at night with gammahydroxybutyrate. Patients with these diseases sleep poorly and generate little SWS. SWS and hibernation are thought to be on a continuum of energy conservation. Thus, the induction of SWS may retard the degenerative process by depressing cell metabolism and by directing energy utilization to vital cell functions. In this way, GHB-induced SWS may duplicate the effects of hibernation and extend biologic time.

Topics: Alzheimer Disease; Animals; Brain; Dementia; Energy Metabolism; Humans; Nerve Degeneration; Parkinson Disease; Sleep Stages; Sodium Oxybate

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid β, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Anesthetics; Circadian Rhythm; Female; Humans; Kinetics; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Pilot Projects; Sleep; Sleep Wake Disorders; Sodium Oxybate

The chronic decrease of brain amyloid-β (Aβ) peptides is an emerging therapeutic for Alzheimer's disease, but no such treatment has achieved clinical validation yet. In vivo, some brain proteases, including neprilysin, possess the ability of degrading Aβ and experimental data suggest their exploitation in strategies to reduce cerebral Aβ concentration. Previous studies have shown that pharmacologic doses of gamma-hydroxybutyrate (sodium oxybate or Xyrem) induce histone deacetylases (HDACs) inhibition and neprilysin gene expression. Here, we demonstrate that brain neprilysin overexpression induced in vivo by repeated gamma-hydroxybutyrate autoadministration reduces cerebral Aβ contents and prevents cognitive deficits in APPSWE mice. Oral gamma-hydroxybutyrate also counteracted phosphoramidon-induced brain neprilysin inhibition and Aβ accumulation. HDACs activities in SH-SY5Y cells were inhibited by gamma-hydroxybutyrate which did not affect amyloid peptide precursor intracellular domain. Together, our results suggest that gamma-hydroxybutyrate, acting via HDAC inhibition, upregulates neprilysin to reduce Aβ level and related memory deficits. Because gamma-hydroxybutyrate doses used herein are clinically relevant, our data suggest that chronic oral administration of gamma-hydroxybutyrate or its analogs may be considered for strategies against presymptomatic or established Alzheimer's disease.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cells, Cultured; Cognition; Disease Models, Animal; Female; Gene Expression; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Mice; Molecular Targeted Therapy; Neprilysin; Sodium Oxybate

Elevated levels of oxidative stress or decreased antioxidant defense mechanisms may underlie the regionally increased oxidative damage to brain observed in many neurodegenerative disorders. Phase I detoxification pathways for reactive aldehydes generated from lipid peroxidation include aldehyde dehydrogenases, alcohol dehydrogenases and aldo-keto reductases (AKR). In the present study, we examined the cellular expression of AKR family member, succinic semialdehyde reductase (AKR7A2) that reduces toxic aldehydes as well as catalyzing the biosynthesis of the neuromodulator gamma-hydroxybutyrate (GHB). Our results show that in the cerebral cortex and hippocampus, AKR7A2 is primarily localized to glial cells, astrocytes and microglia. In the midbrain, AKR7A2 was found in glia and neuromelanin-containing neurons of the substantia nigra, and the periaqueductal gray. In sections of cerebral cortex and hippocampus from patients with AD and DLB, AKR7A2 immunoreactivity was elevated in reactive astrocytes and microglial cells. Furthermore, total AKR7A2 protein levels were elevated in the cerebral cortex of patients with AD versus control individuals. Our data suggest that reactive gliosis, as a response to injury, may affect GHB neuromodulatory pathways in neurodegenerative disease and elevate aldehyde detoxification pathways.

Topics: Aged; Alzheimer Disease; Animals; Astrocytes; Brain; Cell Compartmentation; Cerebral Cortex; gamma-Aminobutyric Acid; Hippocampus; Humans; Hydroxybutyrate Dehydrogenase; Immunohistochemistry; Lewy Body Disease; Male; Microglia; Neurodegenerative Diseases; Neuroglia; Neurons; Rats; Rats, Sprague-Dawley; Sodium Oxybate; Up-Regulation