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Sleepless in Captivity: Insomnia Kills the Von Economo Neurons

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27 February 2024

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28 February 2024

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Abstract
Forensic hospitals throughout the country house individuals with severe mental illness and history of criminal violations. Insomnia affects 67.4% of hospitalized patients with chronic neuropsychiatric disorders, indicating that these conditions may hijack human somnogenic pathways. Conversely, somnolence is a common adverse effect of many antipsychotic drugs, further highlighting a common etiopathogenesis. The role of dysfunctional mitochondria in psychopathology is well-established, however, the association of these organelles with sleep physiology is novel. Indeed, reducing neuronal oxidative stress by importing mitochondria from astrocytes, may be the purpose of human slumber. This model may explain mitochondrial dysfunction during anesthesia as well as in the rare genetic disease, fatal familial insomnia. In this narrative review, we focus on the salience network of the brain, a common denominator for insomnia, neuropsychiatric and neurodegenerative disorders. We also discuss mitochondria-protecting strategies, including membrane lipid replacement, natural and synthetic phenazine and phenothiazine derivatives.
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Subject: Biology and Life Sciences  -   Neuroscience and Neurology

Introduction

One of the most common sleep disorders in the United States, primary insomnia, is usually defined as long sleep latency, difficulty staying asleep, prolonged nighttime wakefulness, and/or early morning awakening [1]. In prison, approximately 60% of inmates experience insomnia, a prevalence 6-10 times higher than in the population at large [2]. Moreover, insomnia is present in 67.4% of hospitalized patients with severe mental illness, suggesting that the pathways of sleep and neuropathology are highly intertwined [3].
Forensic psychiatric hospitals admit patients with schizophrenia (SCZ) or schizophrenia-like disorders (SLDs) and criminal violations. Insomnia is common in this population and failure to address this condition may increase healthcare expenditure due to medical complications, including metabolic, cardiovascular, and neurodegenerative disorders. The salience network (SN), comprised of insular cortex (IC), anterior cingulate cortex (ACC) and several subcortical nodes, has recently been implicated in the etiopathogenesis of insomnia, SCZ, and neurodegenerative disorders [4,5,6,7,8,9]. Von Economo neurons (VENS), a special class of large, spindle-shaped cells found only in humans and superior mammals, are believed to drive empathy, social awareness, fairness, and alertness, connecting sleep with the higher brain functions [10,11]. VENS reside in the SN and play a key role in switching the attentional focus from interoception to exteroception as required by each situation.
At the molecular level, incarceration, insomnia, and severe mental illness have been associated with premature cellular senescence, a phenotype marked by increased intracellular iron and mitochondrial depletion [11,12,13,14,15,16,17,18]. Premature cellular senescence may be triggered by activating the master regulator of cellular aging, aryl hydrocarbon receptor (AhR), residing in both the cytosol and mitochondria [19,20,21]. Senescent cells upregulate intracellular iron which in the proximity of cytosolic fats, increases the risk of lipid peroxidation and neuronal demise by ferroptosis [22,23,24]. Ferroptosis is a programmed, cell death induced by iron in the context of antioxidant failure marked by depletion of glutathione peroxidase-4 (GPX-4) [25,26]. GPX-4 is a mitochondrial enzyme which averts ferroptosis by repairing the oxidized phospholipids and cholesterol in mitochondrial and neuronal membranes [27].
Antipsychotic drugs are known for causing somnolence, indicating a likely interference with the human sleep pathways. For example, phenothiazines, induce sleep by antagonizing histamine H1 and alpha1 adrenergic receptors [28]. Clozapine, an AhR-activating ligand, may induce somnolence by altering the expression of circadian clock genes, some of which are controlled by the AhR [29,30]. Aside from clozapine, oxidized cell membrane lipids also bind AhR, possibly interfering with sleep physiology.
The phenothiazine class of antipsychotic drugs are potent inhibitors of cholesterol metabolism as they lower 7-dehydrocholesterol reductase (7DHC), upregulating 7-dehydrocholesterol (7DHC), a lipid which gets incorporated into the plasma and mitochondrial membranes, strengthening the lipid bilayer [31]. For example, trifluoperazine was shown to protect mitochondria by inhibiting membrane permeability and pore formation [32]. Moreover, phenothiazines intercalate themselves into the lipid bilayer of plasma and mitochondrial membranes, inhibiting peroxidation, thus, protecting the neurons from ferroptosis [33,34,35]. Interestingly, chlorpromazine was found effective against prion diseases, emphasizing a likely beneficial role in fatal familial insomnia (FFI) [36].
Dysfunctional mitochondria and impaired oxidative phosphorylation (OXPHOS), increases glycolysis and lactic acid levels, a metabolic pattern characteristic of SCZ or SLDs [37]. Indeed, increased lactate, considered a marker of sleep deprivation, likely activates mitochondrial AhR (mitoAhR), disrupting the organelle [38,39,40]. This is significant as lactate and neuro-metabolism likely comprise another sleep pathway hijacked by mental illness.
To compensate for dysfunctional mitochondria, neurons import these organelles from glial cells, especially the astrocyte [41,42]. In large cells, such as VENS, mitochondria are more vulnerable to damage and autophagic elimination as they undergo more wear and tear during their journey through the long axons of these neurons [43]. Due to their small number (around 193, 000) and their large sizes, VENS are more susceptible to plasma membrane oxidative stress, which may trigger significant pathology even after a limited neuronal loss, a pathology encountered in frontotemporal dementia behavioral variant (bvFTD).
Since mitochondria are crucial for neuronal function, preserving the integrity of these organelles via membrane lipid replacement (MLR) and other natural strategies, is of utmost importance. Microbial phenazines and the novel antioxidant phenothiazine derivatives, offer new opportunities to combat insomnia, psychosis, and neurodegeneration at the level of cell and mitochondrial membranes.

SN in sleep and neuropathology

The SN is comprised of anterior cingulate cortex (ACC) and anterior insular cortex (AIC) which along with subcortical nodes in the hypothalamus, thalamus, striatum, and midbrain process salient stimuli [44,45]. SN functions as a switch between exteroception and interoception or central executive network (CEN) and default mode network (DMN), depending on stimulus relevance [46]. Switching from CEN to DMN and vice versa is impaired in severe mental illness, insomnia, and neurodegenerative disorders [47]. Several antipsychotic drugs are known to lower the assignment of salience to objects and events, restoring the SN function, likely ameliorating both the psychotic symptoms and insomnia [48].
The SN harbors VENs, which are large, corkscrew neurons located in layer V of the IC and ACC. These non-telencephalic cells are believed to drive the prosocial cognition, empathy, and emotional intelligence. As parts of the SN, VENS respond to endogenous or exogenous stimuli in the order of priority. VENS are selectively eliminated in bvFTD, a disorder marked by criminal violations, lack of empathy, poor insight, and sleep impairment [49,50,51,52,53].
Under physiological circumstances, sleep is driven by the ventrolateral preoptic nucleus (VLPO) of the anterior hypothalamus which releases inhibitory neurotransmitters, including, γ-aminobutyric acid (GABA), and galanin [54]. The opposing system, orexin (hypocretin) neurons in the lateral hypothalamus, inhibit VLPO [55,56,57]. In addition, orexin/hypocretin neurons induce wakefulness by blocking the melanin concentrating hormone (MCH), a somnogen released by the hypothalamus and zona incerta [58,59]. Orexin and DA, the key players of saliency, have been implicated in the neuropsychiatric disorders associated with sleep disturbances, including narcolepsy, attention-deficit/hyperactivity disorder (ADHD), and Parkinson’s disease (PD) [60]. Histamine is another wakefulness-promoting neurotransmitter implicated in SCZ and SLDs and a novel target for treating the negative and cognitive symptoms [61].
To better comprehend the pathogenesis of insomnia, it is necessary to study the pathways of wakefulness, a brain state driving self-awareness and probably consciousness [62]. Early studies on this subject have focused on the locus coeruleus, midbrain tegmentum, pons, and parabrachial nucleus, as neurons in these regions are active during wakefulness [63,64]. In the early 1900s, while studying encephalitis lethargica, Constantin von Economo found that lesions in the posterior hypothalamus were associated with sleep, hypothesizing that this area contained the “center of wakefulness” [65,66,67].
FFI, a rare autosomal dominant disease, is marked by hypometabolism and neuronal loss in the thalamus and cingulate cortex, linking this condition to the SN [68]. Indeed, dysfunctional salience perception in FFI is reflected in sleep disturbances, psychiatric disorders, and autonomic dysregulation, pathologies previously linked to AIC and ACC [69,70,71,72]. The role of SN in sleep physiology and pathology is further highlighted by the fact that anesthetics, especially propofol, lower salience processing, inducing sleep [68,69,70,71,72,73,74,75,76,77,78]. Moreover, recent studies on sleep deprived human volunteers and patients with primary insomnia demonstrated altered connectivity in AIC, further linking SN to sleep and wakefulness [79,80]. Furthermore, several preclinical studies are in line with the findings in humans, implicating the SN in slumber homeostasis [74,81].
Aside from insomnia and neuropsychiatric pathology, the SN connectivity is disrupted in neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and bvFTD, suggesting that insomnia and neuropathology are highly intertwined [82,83,84,85,86]. Indeed, dysfunctional AIC and ACC connectivity may account for the criminal violations in patients with bvFTD in which breaking the law may often be the initial dementia symptom [87,88].

bvFTD as a secondary psychopathy

The second most common neurodegenerative disorder after AD, bvFTD, is marked by inappropriate emotional responses and disinhibited behaviors, often leading to criminal violations [52,89]. In forensic institutions, individuals with first incarceration after the age 55 may suffer from bvFTD, an entity difficult to diagnose as memory may remain intact for longer periods of time. As a result, bvFTD is often missed or misdiagnosed as antisocial personality disorder (APD), SCZ, or SLDs [90].
Over the past two decades, the number of senior first offenders has grown in parallel with the prevalence of young-onset dementia (YOD)(emergence of symptoms before age 65), a subgroup of neurodegenerative disorders, which may include bvFTD [91,92]. Indeed, recent studies have revealed that the prevalence of bvFTD has increased from 15/100, 000 in 2013 to 119 per 100, 000 in 2021, mirroring the growing number of forensic detainees with this diagnosis [92,93].
Compared to AD in which 12% of patients exhibit criminal behavior, bvFTD is associated with a crime rate of 54%, suggesting an acquired psychopathy [94]. Frontotemporal lobar degeneration (FTLD), the pathology driving bvFTD, is believed to selectively eliminate the “honesty cells”, VENS, predisposing to impulsivity and criminal violations [50,51]. Indeed, due to their large size, VENs may be particularly vulnerable to oxidative stress and mitochondrial depletion [95]. The latter is likely due to autophagy of damaged organelles traveling through the long VENS axons. Indeed, lysosomal aggregates, hallmarks of hyperactive autophagy, were demonstrated in VENS derived from patients with bvFTD and SCZ, suggesting excessive mitophagy [95,96,97]. Depletion of VENS has been associated with lack of empathy, aggressive behavior, and criminal violations documented in bvFTD and severe mental illness [51,52]. For example, homicide or attempted homicide have been documented in bvFTD, indicating that criminal behavior and murder can sometimes be the earliest manifestation of this disorder [98,99]. Since VENS are only present in large mammals, including humans, great apes, macaques, cetaceans, and elephants, but not in rodents, these cells are difficult to study in vivo [10]. VENS are larger than pyramidal neurons and drive interoceptive awareness, the ability to detect and process internal cues, such as heartbeat, respiration and the overall visceral state [100,101]. VENS are components of the SN, a large neuronal assembly which responds to intrinsic or extrinsic stimuli, shifting attention from CEN to DMN and vice versa [102,103].
Recent transcriptomic studies found that VENS express monoaminergic proteins, including vesicular monoamine transporter 2 (VMAT2) and adrenergic receptor α-1A (ADRA1A), suggesting involvement in autonomic functions, including the circadian rhythm [104,105,106]. Indeed, impaired monoaminergic signaling has been documented in insomnia, bvFTD, SCZ, and SLDs, implicating VENS in these pathologies [107,108,109,110,111].

Sleep and glial cells

Astrocytes, the most numerous brain cells communicate with each other via calcium waves, attaining synchronization with neurons which supports the slow-wave sleep [112,113]. Moreover, astrocytes release somnogenic molecules, including adenosine, lactate, glutamate, GABA, and interleukin-1 (IL-1), which influence the status of neuronal cells, predisposing to sleep [114].
Astrocytes are central to the neurovascular unit (NVU) and bridge the gap between the neuron and brain microvessels, regulating the flow of interstitial fluid through the aquaporin 4 (AQP-4) receptors [115] (Figure 1). The volume of the brain interstitial fluid (ISF) fluctuates in a circadian manner as it flows through the glymphatic system, a mechanism for clearing misfolded proteins during sleep [116]. The glymphatic system can also carry extracellular vesicles containing mitochondria from astrocytes to neurons [117]. Astrocytes support the neurons by generating GPX-4 to avert neuronal death by ferroptosis. GPX-4 functions to repair oxidized lipids and oxysterols, including 7-ketocholesterol (7KCl), toxins that disrupt plasma and mitochondrial membranes, triggering neuronal death [118]. As mitochondria play a key role in sleep homeostasis, insomnia may be the result of plasma or mitochondrial membrane oxidation [119]. Indeed, it has been suggested that sleep is necessary for abrogating neuronal oxidative stress [120].
Intracellular iron is stored in ferritin and released for intracellular needs via ferritinophagy (ferritin autophagy) in lysosomes. Several antipsychotic drugs, including haloperidol, accumulate in lysosomes disrupting ferritinophagy, which in return lowers intracellular iron, averting ferroptosis [121,122] (Figure 2). This may highlight a DA-independent, antipsychotic action of haloperidol, suggesting that dopaminergic blockade is not the only psychosis-deterring mechanism of this drug. Indeed, ferroptosis of hippocampal neurons, documented in AD and severe mental illness, is the likely cause of cognitive impairment and negative symptoms in these conditions [123,124]. Prolonged insomnia was demonstrated to damage the astrocyte which in return may trigger neuronal demise [125]. Moreover, chronic sleep loss was demonstrated to activate both astrocytes and microglia, turning these cells into neurotoxic phenotypes capable of eliminating healthy neurons and synapses [126,127,128].

Mitochondria and aryl hydrocarbon receptor

Recent studies have implicated mitochondria in the pathophysiology of sleep and neurodegenerative disorders, while the role of these organelles in severe mental illness, including SCZ and SLDs, has been previously established [129,130]. Lipid peroxidation of mitochondrial membrane and iron upregulation can trigger ferroptosis and organelle demise [131,132,133,134]. Indeed, lipid peroxides and oxysterols, such as 7KCl, are mitoAhR ligands, contributing to mitochondrial dysfunction and autophagic elimination [135]. AhR is a xenobiotic sensor which regulates cytochrome p450 and binds the environmental toxin, dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). Other AhR ligands, include somnogens, such as phenazines, melatonin, and tryptophan derivatives, which participate in the physiology of sleep, wakefulness, and the circadian rhythm [136,137,138]. In addition, reactive oxygen species (ROS), known to induce sleep via a redox-sensitive potassium channel, are AhR ligands, bringing this transcription factor in the arena of slumber, mental illness, and neurodegeneration [131,139]. Indeed, microbial phenazines, including pyocyanin and 1-hydroxyphenazine, activate AhR, influencing the transcription of many genes, including those involved in sleep regulation [140,141].
The importance of mitochondria in sleep physiology is further substantiated by the organelle involvement in FFI as well as in general anesthesia [142,143]. Indeed, general anesthetics are known to inhibit N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors, while stimulating GABA. NMDA and AMPA upregulate intracellular and mitochondrial calcium, inducing cell and organelle demise [144]. Interestingly, elevated mitochondrial calcium, a characteristic of prion diseases, may link these organelles to FFI [145,146]. Indeed, the prion peptide causes calcium inflow via L-type calcium channels, triggering neuronal damage and apoptosis [147]. In contrast, the typical antipsychotic, chlorpromazine, not only induces sleep, but also exerts anti-prion properties, probably by promoting autophagy of the misfolded protein [148,149,150].
Mitochondrial trafficking from astrocytes to neurons, supports neuronal bioenergetic needs, especially in large pyramidal cells or VENs. Mitochondria can be imported via cell-cell fusion, tunneling nanotubes (cytoskeletal protrusions reaching to other cells) as well as transported by extracellular vesicles [151,152] (Figure 2). Moreover, astrocytes generate GPX-4 from cysteine obtained via the cystine/glutamate antiporter system (Xc−) or by transmethylation of methionine. Glutathione is generated from cysteine and glutathione disulfide (GSSC) [153] (Figure 2).
Mitochondrial trafficking as well as autophagy (mitophagy) occur during sleep, probably explaining the reason most living beings require rest [154]. Interestingly, serotonin (5-HT) promotes mitochondrial transport in hippocampal neurons, suggesting that antidepressant drugs, serotonin reuptake inhibitors (SSRIs), may “exert their action by supplying healthy mitochondria to stressed neurons [155]. This may imply that ROS accumulation during wakefulness may induce slumber to repair oxidized lipids and import mitochondria from glial cells [120,131,139]. In addition, accumulation of intracellular microtubule-associated protein tau (MAPT) in VENS likely impairs mitochondrial transport, contributing to bvFTD pathogenesis [156].

Four cases of bvFTD from our hospital and the community

Case #1 The teacher who shot her neighbor
Ms. KS (initials changed), a Caucasian female, age 68, divorced, retired elementary school teacher, lived alone prior to her admission to Patton State Hospital. Ms. KS did not have a psychiatric history until the age of 56 when she purchased a gun and shot her neighbor in the shoulder. She stated that she attacked the man because he was spying on her and intruded into her house during the night. She was convicted of attempted murder and sent to prison, where her condition deteriorated, prompting transfer to our forensic institution. KS was diagnosed with SCZ and admitted as a forensic detainee.
During her hospital stay, KS was treated with various antipsychotic drugs with minimal symptomatic relief. She was unaware that she did anything wrong and her poor insight and impulsivity were documented during her six years of hospital stay. Because of poor insight, KS never met criteria for the conditional release program (CONREP).
In 2014, KS became more forgetful, required assistance with most activities of daily living (ADLs), and exhibited a change in her dietary preferences. For example, she asked for ice cream daily, although earlier in her life she detested ice cream. In time, KS became more apathetic and often refused to get out of bed. The internal medicine consultant performed a dementia workup, but the laboratory studies came back normal, except for mild anemia, and a vitamin D level of 29.3 nmol/L. KS scored 25/30 on Mini Mental Status Exam (MMSE) and when a Montreal Cognitive Assessment (MoCA) was administered, the score was 23/30, consistent with executive dysfunction. Neuropsychology consult was called, and after a battery of tests, bvFTD was diagnosed.
With this information, the treatment team petitioned the Court, arguing that KS did not benefit from hospitalization in a forensic institution as she was not expected to recover. The judge agreed with the treating clinicians and ordered placement in a facility specialized in dementia.
Due to the numerous clinical and legal ramifications (discussed below), this case was featured in the mass media at the time:
https://www.reuters.com/article/us-crime-dementia-idUSKBN0KE1Q020150105/
https://www.foxnews.com/health/breaking-the-law-may-be-a-sign-of-dementia
https://clbb.mgh.harvard.edu/when-frontotemporal-dementia-leads-to-crime-prosecution-or-protection/
Case #2 The attorney with a sweet tooth
An outpatient we treated in 2013, was a 72 years old, retired attorney, arrested because he stole chocolate from a grocery store while casually conversing with the owner. When confronted, he replied: “what’s the problem, I have a sweet tooth”. According to the family, the patient came across as careless and indifferent of his children and the spouse, being either apathetic or angry and irritable. For example, when he learned that his son-in-law died unexpectedly, he responded by saying “let’s go out to eat”. His eating habits had changed dramatically, according to his wife, consuming mostly sweets which previously he had avoided. When told to eat more nutritious food, he often became angry.
Case #3 The psychiatrist turned a drug dealer
Dr. Joel Stanley Dreyer was a well-respected psychiatrist who practiced in Riverside, California. In 1990s, Dr. Dreyer was diagnosed with bvFTD but continued to practice psychiatry, and in 2010 was convicted for prescribing, selling, and distributing large amounts of addictive painkillers. As a result of careless prescribing, one person died of an overdose and Dr. Dreyer was convicted and served ten years in prison despite having been diagnosed with bvFTD prior to his crime. This case emphasizes that some jurisdictions do not recognize bvFTD as an attenuating circumstance. The court ruling was based on the testimony of the prison psychiatrist who did not challenge the diagnosis of bvFTD but stated that since not all individuals with this disorder engage in criminal behavior, “direct causality” between Dr. Dreyer’s crime and bvFTD could not be established. A detailed history of this case can be found at the link below:
https://story.californiasunday.com/joel-dreyer-criminal-psychiatrist/.
Case #4 The Buick murderer
On July 16, 2003, Mr. GRW, an 83 years old man crashed his Buick LeSabre in an open-air market in Santa Monica, California, killing 10 and injuring 63 individuals. Despite the catastrophic event he caused, GRW did not express remorse, showed indifference, callousness, and lack of empathy. In the court, he appeared apathetic, angry, and unapologetic, stating that he was sorry the dead and injured could not “enjoy the value of their purchases”. No psychiatric evaluation was ordered because there was no previous history, however, criminal behavior may often represent the first symptom of bvFTD. Despite never being diagnosed with a neurodegenerative disorder, people who knew GRW noticed a drastic personality change in the years prior to this event, indicative of bvFTD. His neighbors, friends, and his pastor, described GRW as caring, pleasant, and friendly individual. He had been married for over 60 years, was compassionate, involved in peoples’ lives, and after retirement, volunteered with various civic organizations. Although GRW was never officially diagnosed with bvFTD, this case illustrates the difficulty clinicians encounter because this neurodegenerative disorder affects the executive function, leaving memory intact for many years. Indeed, shortly before his crime, GRW was able to pass his DMV license renewal test, suggesting that his memory was unaffected. Since in California drivers who are 70 or older must renew their driver’s license in person, GRW did not raise a dementia red flag with the DMV worker.

Discussion

Since bvFTD comprises 2.7% of all dementias and in early stages, patients retain their cognitive abilities, this condition is often misdiagnosed as SCZ, depression, or bipolar disorder, and frequently admitted to psychiatric institutions. Patients with bvFTD respond poorly to antipsychotic drugs, are often labeled “treatment resistant”, and prescribed additional psychotropics [157]. Moreover, as criminal behavior is frequently the initial manifestation of bvFTD, clinicians rarely suspect this condition when examining an incarcerated individual. However, there are several characteristics of this disorder which should prompt the clinician to think of a neurodegenerative condition. These include absence of psychiatric history at a younger age, first legal violation after the age of 55, poor insight despite a previously successful life, sudden change in eating habits, altered sleep pattern, lack of empathy, and engaging in criminal acts despite the presence of witnesses.

Mitochondria-protective treatments

The key role of mitochondria in sleep disorders, SCZ, SLDs, and neurodegeneration, highlights the importance of mitoprotective approaches to resuscitate, replace, or increase the import of mitochondria from glial cells. For example, treatment with SSRIs during the early stages of dementias, may delay the onset of cognitive decline. Along this line, a recent study found that treatment with SSRIs slowed the conversion of mild cognitive impairment to frank dementia, suggesting that prophylactic treatment with these agents may be beneficial [158]. In addition, natural anti-ferroptosis drugs and iron chelators, such as halogenated phenazines, may improve the course of neurodegenerative disorders, suggesting novel therapeutic strategies [159,160].

Membrane Lipid Replacement (MLR)

MLR refers to the oral supplementation with natural, cell membrane glycerophospholipids and kaempferol (3,4′,5,7-tetrahydroxyflavone), a natural flavonoid found in tea, broccoli, cabbage, kale, beans, endive, leek, tomato, strawberries, and grapes [161]. Kaempferol is a glycogen synthase kinase-3β (GSK-3β) inhibitor which prevents sleep deprivation-induced cognitive decline [162,163]. Like lithium and several antipsychotic drugs, kaempferol blocks GSK-3β, an enzyme previously implicated in SCZ and circadian rhythm disorders, suggesting that this natural compound may exert antipsychotic properties without the adverse effects of conventional therapeutics [164,165,166,167].
The aim of MLR + kaempferol is gradual replacement of damaged phospholipids and oxysterols from neuronal and/or mitochondrial membranes with natural glycerophospholipids and a polyphenol. Indeed, oxidized membrane lipids have been implicated in SCZ, SLDs, insomnia, and neurodegeneration, while MLR and kaempferol offer a dual mechanism of action: 1) elimination of lipid peroxides and 2) GSK-3β inhibition [168]. Replacing oxidized plasma and/or mitochondrial membrane fats with healthy natural lipids, averts deformation of neuronal membrane and misalignment of neuroreceptors. Conversely, oxidized membrane lipids and ferroptosis alter the biophysical properties of membranes, disrupting neuronal functions [169].

Phenazines and phenothiazine derivatives

Phenazines are nitrogen-containing heterocyclic compounds produced by various marine and terrestrial microorganisms which participate in microbial clearance, iron signaling, and biofilm formation [170]. Phenazines can be natural (bacteria-derived) or synthetic.
Natural phenazines, such as iodinin (1.6-dihydroxy-N5, N10-dioxide phenazine) and myxin, are antibiotics which have been known for several decades [171]. The newer, terpenoid, glycosylated and fused phenazines, are derived from various Streptomyces species and exert antibiotic and anticancer effects. For example, geranylphenazinediol is an inhibitor of human acetylcholinesterase with potential benefit in neurodegenerative disorders without the adverse effects of the manufactured drugs [172]. Other natural phenazines, including baraphenazines, leucanicidin and endophenasides, exert antimicrobial, anticancer activity, and very likely possess antipsychotic properties [173,174,175].
Synthetic phenazine derivatives consist of over 6,000 compounds, exerting antimicrobial, antiparasitic, neuroprotective, anti-inflammatory, and anticancer activities [176,177,178]. To the best of our knowledge, natural or synthetic phenazines have not been tested for SCZ, insomnia, or neurodegeneration. Pontemazines A and B are neuroprotective phenazine derivatives which in animal studies have rescued hippocampal neurons from glutamate cytotoxicity, highlighting their pro-cognitive properties which could benefit patients with negative symptoms of SCZ or neurodegenerative disorders [176].
Synthetic phenazines exert antioxidant and radical-scavenging properties, inhibit lipid peroxidation, suggesting beneficial effects in severe insomnia, mental illness and neurodegeneration [179,180] (Figure 3). Moreover, halogenated phenazines act as iron chelators, likely preventing neuronal ferroptosis [181]. We believe that Pontemazines and halogenated phenazines should be assessed for antipsychotic/anti-neurodegenerative properties.
From the biochemical standpoint, phenazines are almost identical to phenothiazine antipsychotics and likely possess similar properties (Figure 4). Phenothiazines are typical antipsychotic drugs utilized primarily for SCZ and SLDs which block dopaminergic transmission at the level of postsynaptic neuron. Several phenothiazines influence other receptors, including adrenergic, histaminergic, and cholinergic, exerting various clinical effects as well as adverse reactions. Aside from psychotic disorders, phenothiazines are also used for the treatment of migraine headaches, hiccups, nausea, vomiting, and cancer [182]. Like phenazines, phenothiazines intercalate themselves into the lipid bilayer of plasma and mitochondrial membranes, disrupting the curvature and receptor alignment on neuronal/mitochondrial surfaces [183] (Figure 3). In contrast, oxidized lipids, including 7-ketocholesterol (7KCl), form looped structures, generating membrane curvatures and pores, that may trigger cell death [184].
Antioxidant phenothiazine and their derivatives have recently been developed for cancer, cardiovascular disease (CVD), Mycobacterium leprae and other antibiotic-resistant microbes [185,186].
Phenothiazine derivatives exert anti-peroxidation properties and protect against lipid pathology and ferroptosis, suggesting efficacy as antipsychotic drugs [187]. In addition, antioxidant phenothiazines are likely beneficial for insomnia and neurodegenerative disorders, suggesting that these compounds should be tested for neuropsychiatric pathology [186].
Propenylphenothiazine is a potent antioxidant with electron-donor capability that could prevent gray matter loss, a hallmark of SCZ and SLDs [188,189]. Electron-donating psychotropic drugs have been known to preserve the brain volume, suggesting that propenylphenothiazine may treat psychosis, without reducing the gray matter volume. The majority of conventional antipsychotic drugs are electron-acceptors which often lower the brain volume as documented by many neuroimaging studies [190,191,192,193]. An even newer category of tetracyclic and pentacyclic phenothiazines with antioxidant properties have recently been developed, suggesting likely efficacy for cognitive impairment and negative SCZ symptoms [194]. Moreover, the N10-carbonyl-substituted phenothiazines were demonstrated to inhibit lipid peroxidation, suggesting superior antipsychotic efficacy [187].

Mitochondrial transfer and transplantation

The early studies on mitochondrial transplantation, from the 1980s, utilized co-incubation of various cell types with naked mitochondria, hoping that cells would internalize the organelles from the extracellular environment [195]. Later, HeLa cells and mesenchymal stem cells were used as mitochondrial sources and found that successful organelle uptake occurred in a short time interval of 1-2 hours [196,197,198]. At present, mitochondrial transplantation into cardiomyocytes has been accomplished successfully and confirmed by mitochondrial DNA (mtDNA) detected in host cells [199,200].
Mitochondrial transplantation and neuronal rescue from ferroptosis have been performed successfully in both animals and humans, suggesting a novel strategy for neurometabolic disorders [201]. To our knowledge, mitochondrial transplantation has not been attempted in sleep disorders, while in mental illness, it has been tried in animal models only [132]. Trafficking mitochondria from astrocytes and microglia to neurons can take place spontaneously after brain injuries, reflecting a likely compensatory mechanism to preserve neuronal viability [202]. In addition, it has been established that SSRIs, GJA1-20K, and CD38 signaling can facilitate mitochondrial transfer, emphasizing potential strategies for insomnia, severe mental illness, and neurodegeneration [203,204].

Conclusions

Forensic institutions throughout the country house individuals with severe mental illness and often comorbid insomnia, suggesting overlapping pathogeneses. Loss of neurons due to impaired sleep along with SCZ or SLDs-related gray matter depletion, may trigger the premature development of dementias and other medical complications. These comorbidities increase healthcare expenditures and shorten patients’ lifespan, therefore, identifying and treating these conditions early is essential.
YOD, a category of neurodegenerative disorders which include bvFTD, has been on the rise over the past few decades as evidenced by the increased number of first offenders younger than 65. Selective loss of VENS in bvFTD is likely due to the large size of these cells, predisposing to peroxidation of plasma membrane lipids and mitochondrial loss by autophagy.
At the molecular level, AhR is the equivalent of cerebral VENS, as this protein responds to both endogenous and exogenous ligands, including the lipid peroxides and other insomnia and psychosis-related molecules.
Novel AhR ligands, phenazine and phenothiazine derivatives, as well as mitochondrial transfer or transplantation are potential new strategies for treating psychosis, insomnia, and neurodegeneration without additional loss of brain volume.

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Figure 1. Astrocytes contact cerebral microvessels with their end-feet processes, delineating a pathway for the flow of extracellular fluid, known as the glymphatic system. The volume of interstitial fluid (ISF) in the brain parenchyma varies with the brain work. During high intensity work, AQP-4 water receptors are upregulated in the end-feet, pumping the ISF into astrocytes. This results in low ISF (hypovolemia). During sleep (low intensity brain work), less ISF enters the astrocyte. The circulation of ISF clears the molecular debris (including beta amyloid) from the extracellular space.
Figure 1. Astrocytes contact cerebral microvessels with their end-feet processes, delineating a pathway for the flow of extracellular fluid, known as the glymphatic system. The volume of interstitial fluid (ISF) in the brain parenchyma varies with the brain work. During high intensity work, AQP-4 water receptors are upregulated in the end-feet, pumping the ISF into astrocytes. This results in low ISF (hypovolemia). During sleep (low intensity brain work), less ISF enters the astrocyte. The circulation of ISF clears the molecular debris (including beta amyloid) from the extracellular space.
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Figure 2. Astrocytes support the postmitotic, long-lived, neurons by helping them avert death by ferroptosis and loss of mitochondria. The former is accomplished by exporting GPX-4 to neurons (to repair oxidized lipids), while the latter by exporting healthy mitochondria to neuronal cells (via tunneling nanotubules, extracellular vesicles, or cell-cell fusion). Astrocytes import cystine via cystine/glutamate antiporter (Xc-). Cystine is reduced to cysteine and generates glutathione and GPX-4 (which is transferred to neurons). Cysteine can also be derived from methionine, while glutathione can be generated from cysteine and glutathione disulfide (GSSC). In neurons, iron is stored in ferritin and when needed, ferritin undergoes ferritinophagy (autophagy) in lysosomes, releasing free iron. Iron ingresses the neuron via transferrin receptor 1 (TRF-1), while the excess intracellular iron is eliminated via ferroportin.
Figure 2. Astrocytes support the postmitotic, long-lived, neurons by helping them avert death by ferroptosis and loss of mitochondria. The former is accomplished by exporting GPX-4 to neurons (to repair oxidized lipids), while the latter by exporting healthy mitochondria to neuronal cells (via tunneling nanotubules, extracellular vesicles, or cell-cell fusion). Astrocytes import cystine via cystine/glutamate antiporter (Xc-). Cystine is reduced to cysteine and generates glutathione and GPX-4 (which is transferred to neurons). Cysteine can also be derived from methionine, while glutathione can be generated from cysteine and glutathione disulfide (GSSC). In neurons, iron is stored in ferritin and when needed, ferritin undergoes ferritinophagy (autophagy) in lysosomes, releasing free iron. Iron ingresses the neuron via transferrin receptor 1 (TRF-1), while the excess intracellular iron is eliminated via ferroportin.
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Figure 3. The lipid bilayer of neuronal membrane is easily oxidated when intracellular iron is upregulated. Oxysterols, including 7-Ketocholesterol (a toxic oxide), and oxidated phospholipids alter the biophysical properties of cell membranes, disrupting neurotransmission. In addition, oxidized lipids activate AhR, triggering premature neuronal senescence. Phenazines, Phenothiazines, and their derivatives, intercalate themselves into the lipid bilayer, repairing the lipids in cellular and/or mitochondrial membranes.
Figure 3. The lipid bilayer of neuronal membrane is easily oxidated when intracellular iron is upregulated. Oxysterols, including 7-Ketocholesterol (a toxic oxide), and oxidated phospholipids alter the biophysical properties of cell membranes, disrupting neurotransmission. In addition, oxidized lipids activate AhR, triggering premature neuronal senescence. Phenazines, Phenothiazines, and their derivatives, intercalate themselves into the lipid bilayer, repairing the lipids in cellular and/or mitochondrial membranes.
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Figure 4. Phenazine vs. Phenothiazine: similarities and differences.
Figure 4. Phenazine vs. Phenothiazine: similarities and differences.
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