Epidrugs in the Therapy of Central Nervous System Disorders: A Way to Drive on?

Abstract

The polygenic nature of neurological and psychiatric syndromes and the significant impact of environmental factors on the underlying developmental, homeostatic, and neuroplastic mechanisms suggest that an efficient therapy for these disorders should be a complex one. Pharmacological interventions with drugs selectively influencing the epigenetic landscape (epidrugs) allow one to hit multiple targets, therefore, assumably addressing a wide spectrum of genetic and environmental mechanisms of central nervous system (CNS) disorders. The aim of this review is to understand what fundamental pathological mechanisms would be optimal to target with epidrugs in the treatment of neurological or psychiatric complications. To date, the use of histone deacetylases and DNA methyltransferase inhibitors (HDACis and DNMTis) in the clinic is focused on the treatment of neoplasms (mainly of a glial origin) and is based on the cytostatic and cytotoxic actions of these compounds. Preclinical data show that besides this activity, inhibitors of histone deacetylases, DNA methyltransferases, bromodomains, and ten-eleven translocation (TET) proteins impact the expression of neuroimmune inflammation mediators (cytokines and pro-apoptotic factors), neurotrophins (brain-derived neurotropic factor (BDNF) and nerve growth factor (NGF)), ion channels, ionotropic receptors, as well as pathoproteins (β-amyloid, tau protein, and α-synuclein). Based on this profile of activities, epidrugs may be favorable as a treatment for neurodegenerative diseases. For the treatment of neurodevelopmental disorders, drug addiction, as well as anxiety disorders, depression, schizophrenia, and epilepsy, contemporary epidrugs still require further development concerning a tuning of pharmacological effects, reduction in toxicity, and development of efficient treatment protocols. A promising strategy to further clarify the potential targets of epidrugs as therapeutic means to cure neurological and psychiatric syndromes is the profiling of the epigenetic mechanisms, which have evolved upon actions of complex physiological lifestyle factors, such as diet and physical exercise, and which are effective in the management of neurodegenerative diseases and dementia.

Epigenetic and gene therapy in human and veterinary medicine

“…The use of epigenetic drugs (epi-drugs) and epigenetic diet (epi-diet) is often studied in the context of diseases such as cancer or neurological disorders [ 5 , 32 ]. From this perspective, the safety and efficacy of these compounds for long-term use, especially in the context of nutrition, need further investigation because physicians vary on potential side effects that must be carefully considered [ 33 ]. For example, DNA methyltransferase inhibitors, 5-azacytidine (5-aza) or decitabine, have been studied for their potential for cancer treatment and could have implications in epigenetic regulation [ 34 ].…”

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

“…The possible use in the future of drugs or interventions capable of modifying epigenetic alterations contributing to post-menopausal conditions/diseases in a controlled manner (e.g., removal, addition) may be a feasible avenue for research going forward. Such drugs have been proposed to be applied in conditions affecting bone [210], cancer [211,212], neurodegenerative disorders [213,214], cardiovascular conditions [215,216], and healthy aging [217]. The development of such "epi-drugs" is not without challenges [218], particularly since such interventions will have to be personalized for post-menopausal conditions that arise in different tissues, may not result from a single phenotypic pattern, and may occur in conjunction with multiple co-morbidities as the individual ages.…”

Epigenetics of Trauma Transmission and Fetal Alcohol Spectrum Disorder: What Does the Evidence Support?

“…With limited resources, we believe it is important to target interventions where the most benefit stands to be gained. While future therapeutic interventions may one day target changes to the epigenome, the development of epidrugs (drugs that target DNA methy-lation and histone acetylation) to treat psychological trauma remains in its infancy [146]. Given the impact of social transmission, targeting the social determinants of health would likely have a more far-reaching impact.…”