Epigenetic and pharmacological targeting of neuroinflammation

Epigenetic and pharmacological targeting of neuroinflammation

Our cells are filled with intracellular and surface cell receptors (Berg & Clarke, 2018). These receptor proteins are delineated by structure and bind to a variety of substances responsible for creating a reaction or lack thereof. When a ligand binds to the appropriate receptor, signal transduction activates the receptor and produces a biological response ( Berg & Clarke, 2018). Changes in shape or activity after binding allow signal transmission outside the cell or significant changes within the cell, creating an altered chemical when binding to a ligand-gated-ion channel ( Berg & Clarke, 2018). This post will discuss the agonist/ antagonist spectrum of psychopharmacological agents, G-proteins and ion-gated channels, and epigenetics and their relevance to practice.

Agonists act like ligands, binding to receptors and causing action (Berg & Clarke, 2018). Ligands or agonists consist of pharmaceuticals, drugs, light, hormones, and nerve impulses. Ligands and agonists jump in and out of receptors, increasing signaling or changes in the cell. Antagonists block the standard action of ligands, preventing a response from the receptor (Berg & Clarke, 2018). Competitive antagonists bind to receptors and prevent ligands from attaching to its preferred receptor, inhibiting stimulation, and leaving the receptor unchanged (Berg & Clarke, 2018). Naloxone is a competitive antagonist to opiate receptors London, 2017). The naloxone has a stronger affinity for the receptor, making it more desirable. The medication discontinues the effects of the opiates by taking their place on the receptor. The higher the dose of opiates circulating the more naloxone required. Due to the excess amount of continued competition for receptors, some patients require multiple doses of naloxone before regaining the ability to breath or regain consciousness (London, 2017).

G-protein coupled receptors (GPCRs) target 30-50% of psychotropic medications (Stahl, 2013). As the most abundant protein family, GPCR ligands include neurotransmitters such as serotonin, norepinepherine, and dopamine. After aligand binds to a GPCR, the GPCR undergoes a conformational change (London, 2017). Alpha subunit exchanges Guanyl nucleotide phosphates, GTP, GPP, and Alpha unit disassociates and regulates target proteins (London, 2017). Regulation of neurotransmission is imperative in medication management (London, 2017). The target proteins can then relay signals via a second messenger, and GTP is finally hydrolyzed to GPP (Lambert, 2004). G-protein receptors tend to have a delay in effect due to a requirement for the accumulation of changed cellular function (London, 2017).

Ion gated channel linked receptors open and close in response to a chemical message changing signal transduction in the synaptic cleft. These ion channels act like pores in the cellular membrane to allow ion passage (Stahl, 2013). Transmembrane ion channels open and close in response to the binding of a ligand, differentiated by shape. The binding will cause the channel to open or close, changing the protein conformation of the entire structure (Berg & Clarke, 2018). When channels open, ions like potassium, sodium, chloride, and calcium can travel through and change the electrical process creating an intracellular electrical response (Berg & Clarke, 2018). Psychopharmacology relies heavily on these ion channels in medication management. Ion-channel linked receptors act along an agonist spectrum; medications can produce conformational changes in these receptors to create any state of the agonist spectrum (Stahl, 2013).

The genetic material in the body is referred to as a genome (Stahl, 2013). Every cell in the body carries the same DNA but only expresses specific genes required for its domain (Stahl, 2013). For this reason, cells in the dermis only produce cells required to maintain and rejuvenate the dermis. Epigenetics is the reason why skin cells differ from brain cells or cardiac cells. Epigenetics is a term used for the external modifications to the DNA affecting the way it is recognized by cells (Stahl, 2013). There are thee different methods of epigenetics, DNA myelination, histone acetylation, and microRNA (Stahl, 2013). Genomes are affected by different exposures during development, environmental chemicals, drugs or pharmaceuticals, aging, and diet (Stahl, 2013). Alterations in genes may result from these exposures and be passed on to offspring causing a change in the epigenome (Stahl, 2013).

Psychotropic medications target specific molecular sites to increase neurotransmission. After neurotransmitters release from neurons, they are quickly recollected and utilized again for neurotransmission (Stahl, 2013). The five essential sites of action for psychotropic medications are 12-transmembrane-region transporter, 7-transmembrane-region-G-protein linked, enzymes, 4-transmembrane-region-ligand-gated ion channel, and 6-transmembrane-region-voltage-gated ion channels (Stahl, 2013).

When cellular alterations occur due to brain injury, neurodegeneration, changes in the extracellular matrix, and changes in voltage and ligand-gated ion channels transpire (Iori, 2018). A variety of molecular changes, regulation of gene expression, and epigenetic modifications take place as well(Iori, 2018). As a result, functional impairments such as epilepsy, developmental delay, cognitive/sensory-motor deficits, and drug refractoriness may occur (Iori, 2018). Many factors affect the outcomes of medication. Through assessment is required to determine environmental issues, incidents of trauma, and relevant health history. Understanding that many factors influence the effectiveness of the psychotropic medication is imperative when determining the appropriate treatment course (Lambert, 2004).

Recreational drug use, in combination with prescription medication, is critical to determine. Like antidepressants, drugs like methylphenidate and cocaine target monoamine transporters; this increases the risk for an oversaturation of serotonin, norepinephrine, or dopamine in the synaptic cleft. Oversaturation can potentially cause an issue for signal transduction in other neurotransmitters (Stahl, 2013). This oversaturation of serotonin may cause a toxic level of serotonin, referred to as serotonin syndrome. Patients with serotonin syndrome/toxicity present with neuromuscular, autonomic, and mental status changes. Stopping drugs that target monoamine transporters will help decrease levels of serotonin and should return the individual to their normal state of health (Foong, Grindrod, Patel, & Kellar, 2018).

In conclusion, neurotransmission is the cornerstone of psychopharmacology. Although enormously complicated, it is imperative providers understand that small changes in cellular function, additional drugs present in the body, and electrolyte imbalances affect prescription medication functions and desired effects. With a shortage of psychiatric prescribers and a mental health crisis around the world, all healthcare providers must have a proper understanding of psychopharmacology and interactions with other body systems.

References

Berg, K. A., & Clarke, W. P. (2018). Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. The international journal of neuropsychopharmacology, 21(10), 962–977. https://doi.org/10.1093/ijnp/pyy071

Foong, A. L., Grindrod, K. A., Patel, T., & Kellar, J. (2018). Demystifying serotonin syndrome (or serotonin toxicity). Canadian family physician Medecin de famille canadien, 64(10), 720–727.

Iori, V. (2018). Epigenetic and pharmacological targeting of neuroinflammation as novel therapeutic interventions for epilepsy. Retrieved from
https://hdl.handle.net/11245.1/98bfe10f-44d2-4f42-bc1b-2f3e605c3ece

Lambert, D. G. (2004). Drugs and receptors, Continuing Education in Anaesthesia Critical Care & Pain, 4(6), 181–184, https://doi.org/10.1093/bjaceaccp/mkh049

London, E. D. (2017). Imaging drug action in the brain. Place of publication not identified: Routledge.

Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY: Cambridge University Press