COVID-19-Related Brain Injury: The Potential Role of Ferroptosis

Figures & data

Table 1 Studies Reporting Neuropsychiatric Diseases and Symptoms Related to COVID-19

References	Country	Study Design	Sample Size	Age	Male (%)	Female (%)	Symptoms or Diseases
Helms et al^Citation24	France	Case series	58	63 years (median)	NR	NR	Symptoms: Agitation (69%); confusion (65%); dysexecutive syndrome (36%)
Varatharaj et al^Citation159	UK	Case report	125	NR	NR	NR	Diseases: Ischemic stroke (46%); intracerebral hemorrhage (7%); encephalopathy (7%); encephalitis (6%)
Paterson et al^Citation160	UK	Case report	43	NR	24 (56%)	19 (44%)	Symptoms: Delirium (23%); confusion (23%); disorientation (23%); psychosis (2%); seizures (2%) Diseases: Encephalopathy (23%)
Hao et al^Citation161	China	Case-control study	10	37.4±12.6 years	6 (60%)	4 (40%)	Symptoms: Impulsivity (50%); insomnia (50%); depression (40%); anxiety (30%) Diseases: Dysosmia (20%); dysgeusia (10%); posttraumatic stress disorder (50%)
Li et al^Citation32	China	Retrospective study	219	53.3±15.9 years	130 (59.4%)	89 (40.6%)	Diseases: Ischemic stroke (4.6%); intracerebral hemorrhage (0.5%)
Zhang et al^Citation162	China	Cross-sectional study	57	46.9±15.37 years	29 (50.9%)	28 (49.1%)	Symptoms: Depression (29%); anxiety (21%); depression comorbid with anxiety (21%)
Giacomelli et al^Citation163	Italy	Cross-sectional study	59	60 years (median)	40 (67.8%)	19 (32.2%)	Disease: Olfactory and taste disorders (33.9%)
Nalleballe et al^Citation164	USA	Cohort study	40469	18–50 years (48.7%) 51–80 years (41.8%)	22063 (55%)	18364 (45%)	Symptoms: Headache (3.7%); sleep disorder (3.4%) Diseases: Encephalopathy (2.3%); Olfactory and taste disorders (1.2%); stroke and transient ischemic attack (1.0%); dizziness (0.9%); extrapyramidal and movement disorder (0.7%); seizures (0.6%); polyneuropathy (0.6%); nerve root and plexus disorder (0.4%)

Abbreviation: NR, not reported.

Table 2 Evidence Supporting the Invasion of SARS-CoV-2 into the Central Nervous System

Researchers	Study Design	Main Findings	References
Moriguchi et al	Case report	The first case of COVID-19-related meningitis was reported, and SARS-CoV-2 RNA was detected in cerebrospinal fluid.	[165]
Dinkin et al	Case report	On MRI, two patients who developed cranial neuropathy associated with SARS-CoV-2 infection and had perineural or cranial nerve abnormalities were reported.	[166]
Kadono et al	Case report	Reported a COVID-19 patient with anosmia and transient cerebral edema, suggesting a neurological invasion of SARS-CoV-2.	[39]
Chiu et al	Case report	A case of COVID-19-related anosmia with definite atrophy of the olfactory bulb, indicating a possible neurological marker of coronavirus infection.	[44]
Jiang et al	Original research	SARS-CoV-2 RNA was isolated from lung and brain tissue from the mouse model transgenic for SARS-CoV-2 hACE2.	[167]
Chen et al	Original research	ACE2 is relatively highly expressed in certain locations in the brain, such as the choroid plexus and the paraventricular nucleus of the thalamus.	[168]
Qi et al	Original research	The substantia nigra and cortex are predicted to be high-risk tissues for SARS-CoV-2 infection.	[169]
Buzhdygan et al	Original research	The SARS-CoV-2 spike protein altered the barrier function in 2D static and 3D microfluidic in vitro models of the human blood-brain barrier.	[170]
Song et al	Original research	Using mice overexpressing human ACE2, the neuroinvasion of SARS-CoV-2 in vivo was demonstrated.	[171]
Paniz-Mondolfi et al	Autopsy research	The ultrastructure of the SARS-CoV-2 viral particles was found in the neural and capillary endothelial cells.	[172]
Puelles et al	Autopsy research	The genetic material SARS-CoV-2 was quantitatively detectable in brain tissue samples from 8 (36%) of 22 patients who died from COVID-19.	[173]
Meinhardt et al	Autopsy research	Demonstrated the presence of SARS-CoV-2 RNA and protein in the nasopharynx and brain of patients who died from COVID-19.	[42]
Martin et al	Autopsy research	Pathological features confirmed signs of hypoxia and SARS-CoV-2 brain invasion.	[174]

Abbreviations: COVID-19, coronavirus disease 2019; hACE2, human angiotensin-converting enzyme-2; MRI, magnetic resonance imaging; SARS-CoV-2, coronavirus-2 virus of the severe acute respiratory syndrome.

Figure 1 SARS-CoV-2 infection can cause brain damage through three possible routes. COVID-19 infection causes various brain injuries and diseases (eg, hypoxic brain injury, encephalitis, hemorrhagic necrotizing encephalopathy, acute disseminated encephalomyelitis, and acute stroke). SARS-CoV-2 invades the brain likely through three routes: (1) the vascular pathway where SARS-CoV-2 damages the blood-brain barrier to invade the brain via blood or lymphatic circulation; (2) the peripheral nerve pathway in which SARS-CoV-2 infects the olfactory bulb, the trigeminal nerve, the vagus nerve, and finally the brain through trans-neuronal or retrograde axonal transport; and (3) the cerebrospinal fluid pathway, SARS-CoV-2 can enter the brain through circulating cerebrospinal fluid to trigger a series of proinflammatory and immune responses that eventually result in various brain injuries with neuropsychiatric symptoms.

Figure 2 The potential role of ferroptosis in COVID-19-related brain injury. After SARS-CoV-2 infection, transferrin receptors recognize transferrin that carries Fe³⁺, which enters cells through endocytosis to form endosomes. IL-6 promotes ferritin synthesis, which stores Fe³⁺ and releases Fe³⁺ through ferritinophagy; after that, the endoplasmic reticulum metal reductase Steap3 reduces Fe³⁺ into Fe²⁺ to form LIP. GPX4 protects the cell against lipid peroxidation and inhibits ferroptosis. Under iron overload conditions combined with GPX4 depletion or inhibition, mitochondria generate large amounts of ROS, leading to lipid peroxidation, cell membrane damage, and ferroptosis. Excess ROS depletes intracellular GSH, and this depletion forms a positive feedback loop and aggravates lipid peroxidation. During this peroxidation, damage-associated molecular patterns and alarmins (eg, HMGB1, IL-33, TNF-α, IL-1 β, and IL-6) are released that activate NF-kB and other proinflammatory signaling pathways, eventually leading to neuroinflammation and cell death. SARS-CoV-2 infection can damage the brain, resulting in BBB disruption and bleeding accompanied by a cytokine storm.

Table 3 Potential Therapeutic Targets for COVID-19-Related Brain Injury

Potential Therapeutic Targets	Molecular Mechanisms	Potential Drugs	References
Iron uptake	Inhibits the expression of iron transporters and the activity of Fe^2+/H^+ cotransporters	Antimalarial drugs	[135]
ROS	Inhibits lipid peroxidation and decreases lipid ROS in cellular membranes	Antioxidants (eg, tocotrienol, vitamin E, Fer-1, liprostatin-1, zileuton)	[71,83,84,108,110,175]
LIP	Binds to free iron to inactivate iron-containing enzymes and decreases iron accumulation to inhibit Fenton reaction	Iron chelators (eg, deferoxamine, deferiprone, PBT434, minocycline, VK28,2,2’-dipyridyl)	[71,94–98,128]
Nrf2/KEAP1 pathway	Activates the Nrf2-dependent and Nrf2-independent pathways	(-)-Epicatechin (a brain-permeable flavanol)	[88,143,144]
GPX4-GSH pathway	Enhances GPX4 activity by upregulating its transcription	Se	[79]

Abbreviations: Fer-1, ferrostatin-1; GPX4, glutathione peroxidase 4; GSH, glutathione; KEAP1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor E2-related factor 2; LIP, liable ferrous iron pool; ROS, reactive oxygen species.

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