CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 15, Issue 2, 2016

We know that within the complex mammalian gut is any number of metabolic biomes. The gut has been sometimes called the “second brain” within the “gut-brain axis”. A more informative term would be the gut-brain metabolic interactome, which is coined here to underscore the relationship between the digestive system and cognitive function or dysfunction as the case may be. Co-metabolism between the host and the intestinal microbiota is essential for life’s processes. How diet, lifestyle, antibiotics and other factors shape the gut microbiome constitutes a rapidly growing area of research. Conversely, the gut microbiome also affects mammalian systems. Metabolites of the gut-brain axis are potential targets for treatment and drug design since the interaction or biochemical interplay results in net metabolite production or end-products with either positive or negative effects on human health. This review explores the gut-brain metabolic interactome, with particular emphasis on drug design and treatment strategies and how commensal bacteria or their disruption lead to dysbiosis and the effect this has on neurochemistry. Increasing data indicate that the intestinal microbiome can affect neurobiology, from mental and even behavioral health to memory, depression, mood, anxiety, obesity, cravings and even the creation and maintenance of the blood brain barrier.

Retinal adhesion mechanisms in mammals are quite complex and multifactorial in nature. To date, these mechanisms are incompletely understood due to a variety of chemical, physical, and physiological forces impinging upon retinal tissue: retinal pigment epithelium, nearby tissues as sclera and vitreous, the subretinal space, and the highly complex interphotoreceptor matrix that fills subretinal space. The adhesion of the retina to the choroid, rather than anatomical, is a dynamic process, as the retina detaches a few minutes after life ceases. The adhesion mechanisms described in the literature, such as intraocular pressure and the oncotic pressure of the choroid that seems to push the retina towards the choroid, the delicate anatomical relationships between the rod and cone photoreceptors, the retinal pigment epithelium, the existence of a complex material called interphotoreceptor matrix, as well as other metabolic and structural factors, still cannot explain the remarkable features observed in the adhesion mechanisms between the photoreceptor layer and retinal pigment epithelium cells. The unexpected intrinsic property of melanin to absorb light energy and transform it into chemically based free energy can explain normal adhesion of the sensory retina to the pigment epithelium. In this article, we explore and highlight this explanation, which states that it is definitely able to provide a new treatment avenue against devastating neurodegenerative properties.

Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD. For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aβ) treatments (amyloid-β protein precursor (APP) regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

Microglial cells are extremely important for homeostasis of the CNS. Upon brain damage, microglia become reactive in response to inflammatory stimuli and lead to the secretion of inflammatory cytokines. Because microglia have the ability of adjusting their steady state to an active phenotype that modulates the CNS environment, chronic activation of microglia has an important role in mediating neuroinflammatory brain diseases. Depending upon the nature and degree of the injury stimulus, microglial activity may alternate, either to acute and mild responses -sometimes beneficial- or chronic and severe that may result in neurodegeneration. In this context, proper and controlled activation of microglia should be considered as a potential neuroprotective strategy against neurodegeneration. More recently, the use of estrogenic compounds to regulate microgliosis has shown promising results, and is currently being investigated due to their potential pharmacologic ability in the regulation of inflammation. In this review, we highlight the role of microgliamediated damage and discuss the effect of neurosteroids in reducing the adverse impact of inflammation in the brain.

The concept of age-related dementias and vascular disorders has now been recognized for over a century. In the present review, we have emphasized on the causes, consequences and the true bases for the treatment and prevention of these disorders. Systematic efforts have been put together to identify the aetiology in each case. Increased efforts have been targeted towards the concept and genetic factors responsible for vascular cognitive impairment and post-stroke dementia in relation with Alzheimer’s disease, which is a consequence of age-related dementia, especially as they hold promise for early prevention and treatment. It has now been well accepted that vascular dementia is not a single disease but a group of conditions with different pathological correlations and pathophysiological mechanisms. The present review represents an amalgamation of several pathophysiological mechanisms producing a very heterogeneous clinical presentation for developing such consequences. We suggest current diagnostic categories and describe clinical parameters according to recently reported studies that document the demographic data in a standardized manner for age-related dementia disorders.