Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies.

Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease.

Increased salt intake in food probably affects the progression of cerebral small vessel disease (CSVD), which justifies the study of disturbances in sodium homeostasis associated with the development of CSVD. We aimed to clarify the role of salt sensitivity and osmotic fragility in the development of CSVD. Erythrocyte salt sensitivity was measured using the modified salt blood test, and osmotic fragility was measured using the classic osmotic fragility test in 73 patients with CSVD (48 women; 60.1 ± 6.5 years) and 19 healthy volunteers (14 women; 56.9 ± 6.4 years). Salt sensitivity and osmotic fragility exhibited a predictive value in relation to CSVD. These parameters were associated with an increase in white matter hyperintensities (P = 0.019 and 0.004, respectively). Their simultaneous use increased their predictive ability for CSVD (P < 0.000001; AUC (95% CI), 0.824 (0.724-0.923)). The possibility of predicting CSVD using erythrocyte salt sensitivity and osmotic fragility indicates the value of the individual glycocalyx buffer capacity in relation to sodium and the activity of sodium channels in the development of CSVD. Increased salt sensitivity and osmotic fragility seem to be risk factors for CSVD.

Nicotinamide riboside rescues angiotensin II-induced cerebral small vessel disease in mice.

AIMS: Hypertension is a leading cause of cerebral small vessel disease (CSVD). Currently, treatments for CSVD are limited. Nicotinamide riboside (NR) can protect against vascular injury and cognitive impairment in neurodegenerative diseases. In this study, the protective effects of NR against angiotensin - (Ang -)-induced CSVD were evaluated. METHODS: To explore the effects of NR in CSVD, C57BL/6 mice were infused with Ang -, and NR was added to the food of the mice for 28 days. Then, short-term memory, blood-brain barrier (BBB) integrity, and endothelial function were detected. Arteriole injury and glial activation were also evaluated. RESULTS: Our data showed that mice infused with Ang - exhibited decreased short-term memory function and BBB leakage due to decreased claudin-5 expression and increased caveolae-mediated endocytosis after 28 days. Furthermore, Ang - decreased the expression of α-smooth muscle actin (α-SMA) and increased the expression of proliferating cell nuclear antigen (PCNA) in arterioles and decreased the expression of neurofilament 200 (NF200) and myelin basic protein (MBP) in the white matter. These CSVD-related damages induced by Ang - were inhibited by NR administration. Moreover, NR administration significantly reduced glial activation around the vessels. CONCLUSION: Our results indicated that NR administration alleviated Ang --induced CSVD by protecting BBB integrity, vascular remodeling, neuroinflammation, and white matter injury (WMI)-associated cognitive impairment.

Influences of the TLR4/NF-κB pathway on memory function and inflammatory factors in rats with cerebral small vessel disease.

OBJECTIVE: To explore the influences of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway on the memory function and inflammatory factors in rats with cerebral small vessel disease (CSVD). MATERIALS AND METHODS: CSVD model in rats was established. Expressions of TLR4/NF-κB-related proteins and inflammatory factors were detected. CSVD rats were treated with the TLR4/NF-κB pathway agonist and inhibitor to evaluate the regulatory effect of TLR4/NF-κB pathway on the expressions of TLR4, NF-κB p50 and NF-κB p65. Moreover, their influences on the cerebral edema, memory function and expressions of inflammatory factors [interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)] in CSVD rats were also analyzed. RESULTS: In model group, the mRNA and protein expressions of TLR4 and NF-κB-related proteins in rat hippocampus were significantly higher than those in sham group (p<0.01), and the expressions of IL-1ß and TNF-αsignificantly increased (p<0.05). The agonist lipopolysaccharide (LPS) significantly increased the proportion of TLR4-positive cells (p<0.01) and protein expression of TLR4 (p<0.01). The inhibitor CLI-095 obviously reduced the proportion of TLR4-positive cells and TLR4 expression (p<0.05). Pyrrolidine dithiocarbamate (PDTC) remarkably reduced the expressions of NF-κB p50 and NF-κB p65 in model group (p<0.05). LPS promoted cerebral edema, leading to memory dysfunction and enhanced inflammatory response in rats of model group. The inhibitor CLI-095+PDTC significantly reduced cerebral edema, lowered memory impairment and relieved inflammatory response in CSVD rats (p<0.05). CONCLUSIONS: The inhibitor of the TLR4/NF-κB signaling pathway can restore memory function and reduce inflammatory response in CSVD rats.

Brief Report: Impact of ART Classes on the Increasing Risk of Cerebral Small-Vessel Disease in Middle-Aged, Well-Controlled, cART-Treated, HIV-Infected Individuals.

BACKGROUND: Cerebral small-vessel disease (CSVD) is a chronic disease accounting for one-third of strokes and the second etiology of dementia. Despite sustained immunovirological control, CSVD prevalence is doubled in middle-aged persons living with HIV (PLHIVs), even after adjustment for traditional cardiovascular risk factors. We aimed to investigate whether exposure to any antiretroviral drug class could be associated with an increasing risk of CSVD. METHODS: The MicroBREAK-2 case-control study (NCT02210130) enrolled PLHIVs aged 50 years and older, treated with combined antiretroviral therapy for ≥5 years, with plasma HIV load controlled for ≥12 months. Cases were PLHIVs with radiologically defined CSVD, and controls were CSVD-free PLHIVs matched for age (±5 years), sex, and year of HIV diagnosis (±5 years). Multivariable conditional logistic regression analyses focused on cumulative exposure to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and/or exposure to integrase inhibitors (yes or no), adjusted for hypertension, CD4 nadir, current CD4/CD8 ratio, and HIV transmission group. RESULTS: Between May 2014 and April 2017, 77 cases and 77 controls (85.7% males) were recruited. PLHIVs' median age was 57.6 years, and median HIV diagnosis year was 1992. The increasing risk of CSVD was not associated with exposure to any ART class. CONCLUSION: No deleterious effect of ART class exposure on the risk of CSVD was found for middle-aged treated PLHIVs.

Spermidine preconditioning ameliorates laurate-induced brain injury by maintaining mitochondrial stability.

Ischemic precondition plays a protective effect during cerebral ischemia. This effect partly depends on the autophagic activity. However, whether the activity of autophagy can exert the protective effects after cerebral ischemia is unclear. In this study, rats were treated with spermidine, an activator of autophagy, and injected with sodium laurate via the internal carotid artery to stimulate cerebral small vessel disease (CSVD). The effects of the spermidine precondition on brain injury were evaluated by behavioural test, histology assay, ultrastructure observation, and autophagic-related signals. Furthermore, the mitochondria of brain tissue were isolated, and mitDNA were extracted. The stability of mitDNA was analyzed by quantitative real-time PCR. Results showed that the penetrating artery of the striatum was damaged. This damage was accompanied by neural inflammation characterized by an increase in Fluoro-Jade C (FJC)-positive cells after sodium laurate injection. Spermidine pretreatment decreased the deletion of mitDNA and the autophagy hyperactivity induced by the laurate injection. Likewise, spermidine reduced the neurological deficit and FJC reactivation of striatum at 48 h after laurate injection. These results suggested sodium laurate injection through the internal carotid artery can induce the pathological features of CSVD characterized by the damage of penetrating artery, neurological deficit, mitochondrial impairment, and autophagic hyperactivity. Pretreatment with spermidine can ameliorate these outcomes. Further study indicated that the protective effect of the spermidine precondition is associated with the maintenance of mitochondrial stability and proper autophagy activity.

HIV protease inhibitor exposure predicts cerebral small vessel disease.

OBJECTIVE: HIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND. DESIGN: Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network. METHODS: We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection. RESULTS: We found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03-7.9) and 2.6 (95% CI 1.03-6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6-70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1-21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age. CONCLUSION: Protease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.