Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats

Abstract

Purpose Cadmium is a heavy metal and environmental toxicant known to act on the central cardiovascular regulatory mechanisms, and one of its brain targets is the rostral ventrolateral medulla (RVLM), a brainstem site that maintains blood pressure and sympathetic vasomotor tone. The present study assessed the hypothesis that cadmium elicits cardiovascular dysregulation by inducing neuroinflammation and microglial activation, two potential cellular mechanisms, in RVLM. Methods Adult male Sprague–Dawley rats were used for measuring cardiovascular responses after intravenous administration of cadmium. We further conducted real-time PCR, immunofluorescence staining, in situ determination of mitochondrial superoxide, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay (ELISA) to identify cytokine and chemokine mRNA expression, microglia activation, superoxide production, and necrotic and apoptotic cell death in RVLM. Results We found animals maintained under propofol anesthesia, intravenous administration of cadmium acetate (4 mg/kg) resulted in an increase, followed by a rebound and a secondary decrease in spontaneous baroreflex-mediated sympathetic vasomotor tone, a progressive reduction in mean arterial pressure and heart rate, alongside augmentation of pro-inflammatory cytokine and chemokine in RVLM. All those cardiovascular and neuroinflammatory events were reversed by pretreatment with an anti-inflammatory drug, pentoxifylline (50 mg/kg, i.p.). There were also concurrent microglial activation, reactive oxygen species production, hypoxia, reduced blood flow, and necrotic and apoptotic cell death in RVLM. Conclusion Based on these biochemical, pharmacological and morphological observations, we conclude that neuroinflammation and microglial activation at RVLM, and their downstream cellular mechanisms, causally underpin cadmium-induced cardiovascular dysregulation.

Protective effects of chlorogenic acid on trimethyltin chloride-induced neurobehavioral dysfunctions in mice relying on the gut microbiota

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Exposure to multiple heavy metals is associated with hypertension: A cross-sectional study in China

“…Neuroin ammation and microglial activation of the RVLM as well as related cellular mechanisms are possible causes of Cd-induced cardiovascular disorders (Tsai et al, 2021). Long-term or increased exposure to Cd causes serious renal dysfunction and possible cardiovascular effects.…”

Acute stress transiently activates macrophages and chemokines in cervical lymph nodes

“…The synthesized cDNA stock was stored at −25 °C until analysis. qPCR was performed on a LightCycler® TaqMan Master (#04735536001, Roche Diagnostics Ltd.) using commercially available TaqMan probes with a dye label (FAM) on the 5′ end and a minor groove binder and a non-fluorescent quencher on the 3′ end, CXCL1 (Rn00578225_m1) [ 23 ], CXCL2(Rn00586403_m1) [ 24 , 25 ], CXCR2(Rn02130551_s1) [ 24 , 26 ], and GAPDH(Rn01775763_g1) [ 27 ] (Thermo Fisher Scientific, Waltham, MA, USA). The thermal cycling conditions provided for the LightCycler® 2.0 System were as follows: enzyme activation: 95 °C for 10 min, 45 cycles of amplification: 95 °C for 10 s, 60 °C for 30 s, and signal detection at 72 °C for 1 s, and cooling at 40 °C for 30 s. Gapdh was used as the reference gene to normalize the expression levels.…”