Saturday, 08.08.2020

Magda Malewska-Kasprzak, Agnieszka Permode-Osip and Janusz K. Rybakowski: Disturbance of the purinergic system in affective disorders and schizophrenia 

Hector Warnes’ comments

 

            This review is one of the latest articles addressing the amazing complexities involved in brain function. It is written with clarity and precision. About 15 % of the brain cells are neurons and 85% are glial cells. The latter are in permanent cross-talk with the former. The adenosine and nucleotide receptors (adenosine 5-triphosphate [ATP]) (the purinergic receptors system [Krüger 2016]) are at the heart of  multiple functions. 

            The activity of astrocytes depends on the release of transmitters, such as glutamate, ATP and adenosine. Further, activation of adenosine receptors is related to antidepressant activity and mitochondrial dysfunction of ATP synthesis may be significant for the pathogenesis of neurological and psychiatric illnesses. Activation of A2 receptors by bupropion is associated with an antidepressant effect while caffeine is an adenosine antagonist. 

            Adenosine promotes sleep. Halassa el al. (2009) found that astrocyes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors. These authors further found  that purinergic stimulates A1 receptor to modulate sleep homeostasis and that individuals with elevated adenosine levels report deeper sleep and exhibit higher Slow Wave Sleep percentages (restorative sleep)

            The effect of adenosine and nucleotide receptors on dopaminergic and glutamatergic neurotransmission would be related to the biochemical dysfunction found in schizophrenia.  ATP is prevalent in neuronal and non-neuronal cells and is synthesized in the mitochondria during oxidative phosphorylation. ATP stimulates intercellular calcium signaling which contributes to synapse formation and neuronal plasticity.  Mitochondrial dysfunction of ATP synthesis may be significant for the understanding of many disorders, including aging and neurological ones.

            It becomes mind boggling when one tries to sort out similar entanglements and interactions of the G protein-coupled receptors (GPCR) which is a superfamily target of 40% of all pharmacological agents, or another protein related to the brain-derived neurotrophic factor (BDNF) which appears to have neurogenic and neuroplastic effects and increases in those patients responding to antidepressant therapy.

            Supporting the comments of Rybakowski el al., Ortiz, Ulrich, Zarate and Machado-Vieira (2015) wrote: "Purinergic effects can impact the activity of other neurotransmitters including the dopaminergic, gamma aminobutyric acid (GABA)-ergic, glutamatergic and serotonergic systems... signaling (genetic, biochemical or functional) at these sites is thought to disturb other neurobiological systems including neuroinflammation..." The latter mechanism is being advanced as of late to understand the effect of  proinflammatory citokines on several psychiatric disorders.  

            As modern  nuclear physicists we are far from formulating a unified theory that would encompass, in one stroke or theorem, all the various factors in illness (genoma, connectoma and epigenoma).  I agree with Ortiz et al. when they subtitled their paper: "A key target for developing improved therapeutics."

 

References:

 

Halassa MM, Florian C, Fellin T, Munoz JR, Lee S-Y, Abel T, Haydon PG, Frank MG. Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss. Neuron 2009; 61: 213-9.

Krügel U. Purinergic receptors in psychiatric disorders. Neuropharmacology 2016; 104: 212-25.

Ortiz R, Ulrich H. Zarate CA, Machado-Vieira R. Purinergic system dysfunction in mood disorders: A key target for developing improved therapeutics. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:117-31.

 

May 30, 2019