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Fulltext Beyond the Primary Infarction: Focus on Mechanisms Related to Secondary Neurodegeneration after Stroke

Ong LK

Int J Mol Sci, 2022 Dec 16;23(24).
PMID: 36555665 DOI: 10.3390/ijms232416024

Recently, a growing body of evidence has indicated that secondary neurodegeneration after stroke occurs at remote regions of the brain that are connected to the primary infarction site [...].
Fulltext Can We Use 2,3,5-Triphenyltetrazolium Chloride-Stained Brain Slices for Other Purposes? The Application of Western Blotting

Sanchez-Bezanilla S, Nilsson M, Walker FR, Ong LK

Front Mol Neurosci, 2019;12:181.
PMID: 31417355 DOI: 10.3389/fnmol.2019.00181

2,3,5-Triphenyltetrazolium chloride (TTC) staining is a commonly used method to determine the volume of the cerebral infarction in experimental stroke models. The TTC staining protocol is considered to interfere with downstream analyses, and it is unclear whether TTC-stained brain samples can be used for biochemistry analyses. However, there is evidence indicating that, with proper optimization and handling, TTC-stained brains may remain viable for protein analyses. In the present study, we aimed to rigorously assess whether TTC can reliably be used for western blotting of various markers. In this study, brain samples obtained from C57BL/6 male mice were treated with TTC (TTC+) or left untreated (TTC-) at 1 week after photothrombotic occlusion or sham surgery. Brain regions were dissected into infarct, thalamus, and hippocampus, and proteins were extracted by using radioimmunoprecipitation assay buffer. Protein levels of apoptosis, autophagy, neuronal, glial, vascular, and neurodegenerative-related markers were analyzed by western blotting. Our results showed that TTC+ brains display similar relative changes in most of the markers compared with TTC- brains. In addition, we validated that these analyses can be performed in the infarct as well as other brain regions such as the thalamus and hippocampus. Our findings demonstrate that TTC+ brains are reliable for protein analyses using western blotting. Widespread adoption of this approach will be key to lowering the number of animals used while maximizing data.
Fulltext Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

Stuckey SM, Ong LK, Collins-Praino LE, Turner RJ

Int J Mol Sci, 2021 Dec 03;22(23).
PMID: 34884906 DOI: 10.3390/ijms222313101

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well-documented that neuroinflammation and immune mediators play a key role in acute and long-term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti-inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post-stroke neuroinflammation, specifically how it affects neuronal tissue and post-stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti-inflammatory therapies, with a particular focus on how failed anti-inflammatories may be repurposed to target SND-associated neuroinflammation.
Editorial: Stress, mood, and fatigue: Tackling "invisible" obstacles in stroke rehabilitation and recovery

Gyawali P, Wong D, Hordacre B, Ong LK, English C

Front Neurol, 2022;13:1121667.
PMID: 36733449 DOI: 10.3389/fneur.2022.1121667
Development of audio-guided deep breathing and auditory Go/No-Go task on evaluating its impact on the wellness of young adults: a pilot study

Kwa EK, Cheong SK, Ong LK, Lee PF

Biomed Tech (Berl), 2024 Apr 25;69(2):141-150.
PMID: 37856824 DOI: 10.1515/bmt-2023-0410

OBJECTIVES: Numerous studies indicate that deep breathing (DB) enhances wellbeing. Multiple deep breathing methods exist, but few employ audio to reach similar results. This study developed audio-guided DB and evaluated its immediate impacts on healthy population via self-created auditory Go/No-Go task, tidal volume changes, and psychological measures.
METHODS: Audio-guided DB with natural sounds to guide the DB was developed. Meanwhile, audio-based Go/No-Go paradigm with Arduino was built to measure the attention level. Thirty-two healthy young adults (n=32) were recruited. Psychological questionnaires (Rosenberg's Self-Esteem Scale (RSES), Cognitive and Affective Mindfulness Scale-Revised (CAMS-R), Perceived Stress Scale (PSS)), objective measurements with tidal volume and attention level with auditory Go/No-Go task were conducted before and after 5 min of DB.
RESULTS: Results showed a significant increment in tidal volume and task reaction time from baseline (p=0.003 and p=0.033, respectively). Significant correlations were acquired between (1) task accuracy with commission error (r=-0.905), (2) CAMS-R with task accuracy (r=-0.425), commission error (r=0.53), omission error (r=0.395) and PSS (r=-0.477), and (3) RSES with task reaction time (r=-0.47), task accuracy (r=-0.362), PSS (r=-0.552) and CAMS-R (r=0.591).
CONCLUSIONS: This pilot study suggests a link between it and young adults' wellbeing and proposes auditory Go/No-Go task for assessing attention across various groups while maintaining physical and mental wellness.
Fulltext Growth Hormone Treatment Promotes Remote Hippocampal Plasticity after Experimental Cortical Stroke

Sanchez-Bezanilla S, Åberg ND, Crock P, Walker FR, Nilsson M, Isgaard J, et al.

Int J Mol Sci, 2020 Jun 26;21(12).
PMID: 32604953 DOI: 10.3390/ijms21124563

Cognitive impairment is common after stroke, and disturbances in hippocampal function are often involved, even in remote non-hippocampal injuries. In terms of hippocampal function, growth hormone (GH) is known to affects plasticity and cognition. We aimed to investigate whether GH treatment after an experimental cortical stroke could enhance remote hippocampal plasticity and the hippocampal-dependent visual discrimination task. C57BL6 male mice were subjected to cortical photothrombotic stroke. Stroke mice were then treated with either saline or GH at 48 h after occlusion for 28 days. We assessed learning and memory using mouse touchscreen platform for the visual discrimination task. We also evaluated markers of neural progenitor cells, synaptic plasticity and cerebrovascular remodelling in the hippocampal formation. GH treatment significantly improved the performance on visual discrimination task after stroke. We observed a concomitant increased number of bromodeoxyuridine-positive cells in the dentate gyrus of the hippocampus. We also detected increased protein levels and density of doublecortin, a neuronal precursor cells marker, as well as glutamate receptor 1 (GLuR1), a synaptic marker. These findings provide further neurobiological evidence for how GH treatment could be used to promote hippocampal plasticity in a remote region from the initial cortical injury, and thus enhance cognitive recovery after stroke.
Triage of urology referrals and outpatient service during COVID-19 pandemic: experience from a single centre in Malaysia

Ong LK, Sivaneswaran L, Mohd Najib A, Devindran M, Say BL, Rohan MJ

Med J Malaysia, 2020 07;75(4):400-402.
PMID: 32724002

In Malaysia, COVID-19 pandemic recorded considerable number of cases. Many hospitals have been converted into COVID-19 centres to manage these cases. The Penang General Hospital was designated as a hybrid hospital to manage both COVID-19 and non-COVID-19 cases. Consequently, services across specialties, including urology have been affected. Triage of referrals was necessary to ensure optimum patient care, thus we designed a triage system to address this situation. A record screening system of patients was also implemented to limit outpatient appointments. We share this early experience in managing urology patients during this pandemic.
Fulltext Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Lee NT, Ong LK, Gyawali P, Nassir CMNCM, Mustapha M, Nandurkar HH, et al.

Biomolecules, 2021 07 06;11(7).
PMID: 34356618 DOI: 10.3390/biom11070994

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.
Fulltext Exploring the relationship between fatigue and circulating levels of the pro-inflammatory biomarkers interleukin-6 and C-reactive protein in the chronic stage of stroke recovery: A cross-sectional study

Gyawali P, Hinwood M, Chow WZ, Kluge M, Ong LK, Nilsson M, et al.

Brain Behav Immun Health, 2020 Dec;9:100157.
PMID: 34589899 DOI: 10.1016/j.bbih.2020.100157

Background: The precise mechanisms underlying the aetiology of post-stroke fatigue remain poorly understood. Inflammation has been associated with clinically significant fatigue across a number of neurological disorders; however, at present there is a lack of evidence regarding the association of fatigue and inflammation in the chronic phase of stroke recovery.
Aims: The aim of this study was to examine fatigue in a cohort of stroke survivors in the chronic phase of stroke, compared with matched controls, and to explore associations between the pro-inflammatory cytokine interleukin-6, high-sensitivity C-reactive Protein and fatigue.
Methods: We performed an exploratory cross-sectional study of 70 people in the chronic phase of stroke recovery, and 70 age matched controls. Fatigue was assessed using the Fatigue Assessment Scale. Interleukin-6 was measured in serum using a commercially available enzyme immunoassay kit. Both outcome measures were assessed contemporaneously.
Results: Clinically significant fatigue, defined as a score ≥24 on the Fatigue Assessment Scale, was reported by 60% of stroke survivors, and 15.7% of controls. The odds of experiencing clinically significant fatigue was 8.04 times higher among stroke survivors compared to control participants (odds ratio 8.045; 95% CI: 3.608, 17.939; P
Fulltext Growth Hormone Promotes Motor Function after Experimental Stroke and Enhances Recovery-Promoting Mechanisms within the Peri-Infarct Area

Sanchez-Bezanilla S, Åberg ND, Crock P, Walker FR, Nilsson M, Isgaard J, et al.

Int J Mol Sci, 2020 Jan 17;21(2).
PMID: 31963456 DOI: 10.3390/ijms21020606

Motor impairment is the most common and widely recognised clinical outcome after stroke. Current clinical practice in stroke rehabilitation focuses mainly on physical therapy, with no pharmacological intervention approved to facilitate functional recovery. Several studies have documented positive effects of growth hormone (GH) on cognitive function after stroke, but surprisingly, the effects on motor function remain unclear. In this study, photothrombotic occlusion targeting the motor and sensory cortex was induced in adult male mice. Two days post-stroke, mice were administered with recombinant human GH or saline, continuing for 28 days, followed by evaluation of motor function. Three days after initiation of the treatment, bromodeoxyuridine was administered for subsequent assessment of cell proliferation. Known neurorestorative processes within the peri-infarct area were evaluated by histological and biochemical analyses at 30 days post-stroke. This study demonstrated that GH treatment improves motor function after stroke by 50%-60%, as assessed using the cylinder and grid walk tests. Furthermore, the observed functional improvements occurred in parallel with a reduction in brain tissue loss, as well as increased cell proliferation, neurogenesis, increased synaptic plasticity and angiogenesis within the peri-infarct area. These findings provide new evidence about the potential therapeutic effects of GH in stroke recovery.
Fulltext Opposing Associations of Stress and Resilience With Functional Outcomes in Stroke Survivors in the Chronic Phase of Stroke: A Cross-Sectional Study

Gyawali P, Chow WZ, Hinwood M, Kluge M, English C, Ong LK, et al.

Front Neurol, 2020;11:230.
PMID: 32390923 DOI: 10.3389/fneur.2020.00230

Stroke survivors report significant levels of psychological distress post stroke. To date, most studies conducted have focused on the relationship between psychological stress and functional outcomes in the acute phase of stroke. However, no studies had considered the role of stress over the chronic phase, where stress may continue to exert negative effects on cognitive and psychological processes. Further, the role of potentially modulatory variables, such as psychological resilience, on stroke outcomes has been understudied. The purpose of this study was to consider the relationships between stress and resilience with functional outcomes in long-term survivors of stroke. People (N = 70) who had experienced a stroke between 5 months and 28 years ago were included in the cross-sectional study, along with age-matched controls (N = 70). We measured stress using both the Perceived Stress Scale and biological markers, and resilience using both the Brief Resilience Scale and the Connor-Davidson Resilience Scale. Stroke outcomes were assessed using the Stroke Impact Scale. We found that, compared with age-matched controls, stroke survivors reported greater levels of perceived stress, and lower levels of resilience. In stroke survivors, both perceived stress and resilience were independently associated with stroke outcomes in linear regression models. In particular, these relationships were observed for cognitive outcomes including mood, memory, and communication. The association between stress and stroke outcome did not differ across time post stroke. Given that resilience is a modifiable psychological construct, future research may consider whether strategies directed at enhancing resilience may improve recovery from stroke. Australia and New Zealand Clinical Trials Registry: ACTRN12617000736347.
More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke

Sanchez-Bezanilla S, Hood RJ, Collins-Praino LE, Turner RJ, Walker FR, Nilsson M, et al.

J Cereb Blood Flow Metab, 2021 09;41(9):2439-2455.
PMID: 33779358 DOI: 10.1177/0271678X211005877

There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.
Fulltext Similar cognitive deficits in mice and humans in the chronic phase post-stroke identified using the touchscreen-based paired-associate learning task

Chow WZ, Ong LK, Kluge MG, Gyawali P, Walker FR, Nilsson M

Sci Rep, 2020 Nov 11;10(1):19545.
PMID: 33177588 DOI: 10.1038/s41598-020-76560-x

For many chronic stroke survivors, persisting cognitive dysfunction leads to significantly reduced quality of life. Translation of promising therapeutic strategies aimed at improving cognitive function is hampered by existing, disparate cognitive assessments in animals and humans. In this study, we assessed post-stroke cognitive function using a comparable touchscreen-based paired-associate learning task in a cross-sectional population of chronic stroke survivors (≥ 5 months post-stroke, n = 70), age-matched controls (n = 70), and in mice generated from a C57BL/6 mouse photothrombotic stroke model (at six months post-stroke). Cognitive performance of stroke survivors was analysed using linear regression adjusting for age, gender, diabetes, systolic blood pressure and waist circumference. Stroke survivors made significantly fewer correct choices across all tasks compared with controls. Similar cognitive impairment was observed in the mice post-stroke with fewer correct choices compared to shams. These results highlight the feasibility and potential value of analogous modelling of clinically meaningful cognitive impairments in chronic stroke survivors and in mice in chronic phase after stroke. Implementation of validated, parallel cross-species test platforms for cognitive assessment offer the potential of delivering a more useful framework for evaluating therapies aimed at improving long-term cognitive function post-stroke.
Fulltext Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke

Zalewska K, Hood RJ, Pietrogrande G, Sanchez-Bezanilla S, Ong LK, Johnson SJ, et al.

Int J Mol Sci, 2021 Jun 22;22(13).
PMID: 34206635 DOI: 10.3390/ijms22136693

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.
Leakage beyond the primary lesion: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke

Hood RJ, Sanchez-Bezanilla S, Beard DJ, Rust R, Turner RJ, Stuckey SM, et al.

J Neurochem, 2023 Dec;167(6):733-752.
PMID: 38010732 DOI: 10.1111/jnc.16008

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-β accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-β around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-β with vasculature and blood-brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-β deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.
Fulltext Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms

Zhao Z, Hood RJ, Ong LK, Pietrogrande G, Sanchez Bezanilla S, Warren KE, et al.

Front Neurol, 2021;12:585189.
PMID: 33841293 DOI: 10.3389/fneur.2021.585189

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O2) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aβ) burden. These findings provide further insight into the pro-cognitive benefits of LOPC.
Fulltext Diets and Cellular-Derived Microparticles: Weighing a Plausible Link With Cerebral Small Vessel Disease

Nassir CMNCM, Ghazali MM, Hashim S, Idris NS, Yuen LS, Hui WJ, et al.

Front Cardiovasc Med, 2021;8:632131.
PMID: 33718454 DOI: 10.3389/fcvm.2021.632131

Cerebral small vessel disease (CSVD) represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger neuroinflammation and the subsequent neurodegenerative cascade. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, Alzheimer disease, and Parkinson disease. Despite being the most common neurodegenerative condition with cerebrocardiovascular axis, understanding about it remains poor. Interestingly, modifiable risk factors such as unhealthy diet including high intake of processed food, high-fat foods, and animal by-products are known to influence the non-neural peripheral events, such as in the gastrointestinal tract and cardiovascular stress through cellular inflammation and oxidation. One key outcome from such events, among others, includes the cellular activations that lead to elevated levels of endogenous cellular-derived circulating microparticles (MPs). MPs can be produced from various cellular origins including leukocytes, platelets, endothelial cells, microbiota, and microglia. MPs could act as microthrombogenic procoagulant that served as a plausible culprit for the vulnerable end-artery microcirculation in the brain as the end-organ leading to CSVD manifestations. However, little attention has been paid on the potential role of MPs in the onset and progression of CSVD spectrum. Corroboratively, the formation of MPs is known to be influenced by diet-induced cellular stress. Thus, this review aims to appraise the body of evidence on the dietary-related impacts on circulating MPs from non-neural peripheral origins that could serve as a plausible microthrombosis in CSVD manifestation as a precursor of neurodegeneration. Here, we elaborate on the pathomechanical features of MPs in health and disease states; relevance of dietary patterns on MP release; preclinical studies pertaining to diet-based MPs contribution to disease; MP level as putative surrogates for early disease biomarkers; and lastly, the potential of MPs manipulation with diet-based approach as a novel preventive measure for CSVD in an aging society worldwide.
Fulltext Neurological impairment caused by Schistosoma mansoni systemic infection exhibits early features of idiopathic neurodegenerative disease

Gasparotto J, Senger MR, Telles de Sá Moreira E, Brum PO, Carazza Kessler FG, Peixoto DO, et al.

J Biol Chem, 2021 08;297(2):100979.
PMID: 34303703 DOI: 10.1016/j.jbc.2021.100979

Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-β peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.

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