Alzheimer's disease as an innate autoimmune disease (AD2 ): A new molecular paradigm.

A new model of Alzheimer's disease (AD) is presented: Alzheimer's disease as an autoimmune disease (AD2 ).  In response to pathogen-/damage-associated molecular pattern-stimulating events (e.g., infection, trauma, ischemia, pollution), amyloid beta (Aß) is released as an early responder cytokine triggering an innate immunity cascade in which Aß exhibits immunomodulatory/antimicrobial duality.  However, Aß's antimicrobial properties result in a misdirected attack upon "self" neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential gradients and anionic charges on outer membrane macromolecules. The subsequent breakdown products of necrotic neurons elicit further release of Aß leading to a chronic, self-perpetuating cycle. In AD2 , amino acid (trp, arg) metabolism is a central control player in modulating AD autoimmunity.  AD2 includes Aß as an important molecular player, but rejects the "amyloid hypothesis," recognizing Aß as a physiologically oligomerizing cytokine and part of a larger immunopathic conceptualization of AD.

Nutrients in Alzheimer's Disease: The Interaction of Diet, Drugs and Disease.

In recent decades, clinical trials in Alzheimer's disease (AD) have failed at an unprecedented rate. The etiology of AD has since come under renewed scrutiny, both to elucidate the underlying pathologies and to identify novel therapeutic strategies. Here, diet has emerged as a potential causative/protective agent. A variety of nutrients, including lipids, minerals, vitamins, antioxidants and sugars as well as broader dietary patterns and microbiotal interactions have demonstrated associations with AD. Although clinical trials have yet to definitively implicate any singular dietary element as therapeutic or causative, it is apparent that dietary preferences, likely in complex synergies, may influence the risk, onset and course of AD. This review catalogs the impact of major dietary elements on AD. It further examines an unexplored reciprocal association where AD may modulate diet, as well as how potential therapeutics may complicate these interactions. In doing so, we observe diet may have profound effects on the outcome of a clinical trial, either as a confounder of a drug/disease interaction or as a generally disruptive covariate. We therefore conclude that future clinical trials in AD should endeavor to control for diet, either in study design or subsequent analyses.

Topically applied linoleic/linolenic acid for chronic migraine.

The topical application of linoleic and linolenic acids is a potential prophylactic approach to migraine via an anti-inflammatory mechanism. We present a 45-year-old woman with chronic migraine without aura. Previous use of abortive or prophylactic therapies including sumatriptan, amitriptyline and topiramate had failed due to lack of efficacy or side-effects, especially vomiting. In search of a topical agent she performed an n-of-1 trial comparing application of linoleic acid (safflower oil) versus oleic acid (olive oil) for migraine relief. She found safflower oil to be effective. Topically applied safflower oil rich in linoleic and linolenic acids may offer a safe, easily applied, well-tolerated, effective anti-inflammatory approach for the prophylactic treatment of chronic migraine.

Vagal stimulation by manual carotid sinus massage to acutely suppress seizures.

Carotid sinus massage, a technique involving digital pressure on the richly innervated carotid sinus, is a time-honoured method for termination of supraventricular tachycardia due to paroxysmal atrial tachycardia. Vagal nerve stimulation, a more recent technique, employs pacemaker stimulation of the vagus as a treatment for refractory epilepsy. This case report discusses the use of carotid sinus massage to abort seizure activity. The patient used manual manipulation of the carotid sinus (similar to cardiology techniques) to suppress seizures, achieving a therapeutic neurological outcome.

A spontaneous recurrent seizure bioassay for anti-epileptogenic molecules.

Drug design in epilepsy is now tackling a new target--epileptogenesis. This is the process whereby a normal brain becomes susceptible to recurrent seizures. One of the stumbling blocks in the design and discovery of new chemical entities as antiepileptogenics is the implementation of an appropriate biological model. Current models, such as the maximal electroshock model, are models of seizures, not models of epileptogenesis. To develop such a model, we have extended and modified a chronic pilocarpine spontaneous recurrent seizure (SRS) model for the purposes of developing a bioassay with which to screen new compounds for putative antiepileptogenic bioactivity.

Functionalized amido ketones: new anticonvulsant agents.

We have reported that functionalized amino acids (FAA) are potent anticonvulsants. Replacing the N-terminal amide group in FAA with phenethyl, styryl, and phenylethynyl units provided a series of functionalized amido ketones (FAK). We show that select FAK exhibit significant anticonvulsant activities thereby providing information about the structural requirements for FAA and FAK bioactivity.