Hepatic Encephalopathy and Melatonin

Abstract

Hepatic encephalopathy (HE) is a severe metabolic syndrome linked with acute/chronic hepatic disorders. HE is also a pernicious neuropsychiatric complication associated with cognitive decline, coma, and death. Limited therapies are available to treat HE, which is formidable to oversee in the clinic. Thus, determining a novel therapeutic approach is essential. The pathogenesis of HE has not been well established. According to various scientific reports, neuropathological symptoms arise due to excessive accumulation of ammonia, which is transported to the brain via the blood-brain barrier (BBB), triggering oxidative stress and inflammation, and disturbing neuronal-glial functions. The treatment of HE involves eliminating hyperammonemia by enhancing the ammonia scavenging mechanism in systemic blood circulation. Melatonin is the sole endogenous hormone linked with HE. Melatonin as a neurohormone is a potent antioxidant that is primarily synthesized and released by the brain's pineal gland. Several HE and liver cirrhosis clinical studies have demonstrated impaired synthesis, secretion of melatonin, and circadian patterns. Melatonin can cross the BBB and is involved in various neuroprotective actions on the HE brain. Hence, we aim to elucidate how HE impairs brain functions, and elucidate the precise molecular mechanism of melatonin that reverses the HE effects on the central nervous system.

Keywords: cognitive impairment; hepatic encephalopathy; hyperammonemia; melatonin; neuroinflammation; neurotransmitter.

Figure 1

Neuropathogenesis of HE on brain dysfunction. HE liver releases excess nitrogenous toxin (NH₃, NH₄⁺) that enters cerebral circulation. Ammonia can cross the BBB and trigger the other pathological response such as activation of aquaporin water channels and damage of BBB’s tight junctions. Astrocytes detoxify ammonia to form glutamine from glutamate by glutamine synthase (GS). Excess glutamine production increases oxidative stress, aquaporin channels’ activation, increases Ca²⁺ influx and GFAP production, and decreases glutamate uptake leading to accumulation of glutamate into the extracellular fluid. Activation of water channels, increased Ca²⁺ influx, and increased glutamine secretion cause astrocyte swelling. On the other hand, accumulated extracellular glutamate enters into neurons, causing glutamate neurotoxicity. Intracellular glutamate impairs glucose metabolism, activates microglial inflammatory cytokines, increases oxidative stress, and inhibits mitochondrial functions, leading to decrease in excitatory neurotransmitters synthesis and release into the synapses. In synaptic transmission increases synthesis and release of inhibitory neurotransmitters impairing the LTP, synaptic plasticity, and reducing synaptic density proteins, leading to cognitive decline and other neuropsychiatric illnesses.

Figure 2

Neuroprotective action of melatonin on HE brain. In the brain, melatonin is synthesized and released from pinealocytes of the pineal gland. Melatonin binds to its receptors and activates various physiological functions such as 1. In astrocytes: Melatonin detoxifies the excess ammonia by activating the Arginase I and II enzyme that prevents glutamine synthesis and glutamate accumulation in extracellular fluid. Furthermore, melatonin prevents neuroinflammation and astrocyte swelling by decreasing the Ca²⁺ influx and inhibiting water channel activation. 2. In a neuron, melatonin inhibits the cAMP/cGMP/PKA/Ry.R/Ca.V/GSK/PP-2A signaling pathway leading to the decreased oxidative stress level, inhibits the microglial activation, and reduces the inhibitory neurotransmitter synthesis and release. Moreover, melatonin regulates glucose metabolism by acting on insulin/GLUT receptors, facilitating synaptic plasticity, LTP, cognition by increasing the synaptic density proteins expression, and increasing the excitatory neurotransmitter release.