Negligible influence of moderate to severe hyperthermia on blood-brain barrier permeability and neuronal parenchymal integrity in healthy men

Shepley, Brooke R; Ainslie, Philip N.; Hoiland, Ryan L.; Donnelly, Joseph E.; Sekhon, Mypinder S.; Zetterberg, Henrik; Blennow, Kaj; Bain, Anthony R.

doi:10.1152/japplphysiol.00645.2020

Cited by 7 publications

(11 citation statements)

References 66 publications

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“…Conversely, Kojima et al [ 11 ] found significant increases in serum BDNF concentration without concomitant changes in S100β following 20 min of hot water immersion. In support, Shepley et al [ 35 ] recently reported that 60 min of moderate-to-severe hyperthermia induced by hot water immersion (+2°C core temperature) has a negligible impact on biomarkers of neurovascular integrity and permeability released from the brain. This highlights the fact that sources other than the brain produce and release BDNF in response to various physiological stimuli [ 17 ].…”

Section: Discussionmentioning

confidence: 86%

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating

et al. 2021

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Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal adaptations. While previous studies suggest that whole-body heating can elevate circulating BDNF concentration, this is not known for local heating protocols. This study investigated the acute effects of whole-body versus local passive heating on serum and plasma BDNF concentration. Using a water-perfused suit, ten recreationally active males underwent three 90 min experimental protocols: heating of the legs with upper-body cooling (LBH), whole-body heating (WBH) and a control condition (CON). Blood samples were collected before, immediately after and 1 h post-heating for the determination of serum and plasma BDNF concentration, platelet count as well as the BDNF release per platelet. Rectal temperature, cardiac output and femoral artery shear rate were assessed at regular intervals. Serum and plasma BDNF concentration were elevated after WBH (serum: 19.1±5.0 to 25.9±11.3 ng/ml, plasma: 2.74±0.9 to 4.58±2.0; p<0.044), but not LBH (serum: 19.1±4.7 to 22.3±4.8 ng/ml, plasma: 3.25±1.13 to 3.39±0.90 ng/ml; p>0.126), when compared with CON (serum: 18.6±6.4 to 16.8±3.4 ng/ml, plasma: 2.49±0.69 to 2.82±0.89 ng/ml); accompanied by an increase in platelet count (p<0.001). However, there was no change in BDNF content per platelet after either condition (p = 0.392). All physiological measures were elevated to a larger extent after WBH compared with LBH (p<0.001), while shear rate and rectal temperature were higher during LBH than CON (p<0.038). In conclusion, WBH but not LBH acutely elevates circulating BDNF concentration. While these findings further support the use of passive heating to elevate BDNF concentration, a larger increase in shear rate, sympathetic activity and/or rectal temperature than found after LBH appears needed to induce an acute BDNF response by passive heating.

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Section: Discussionmentioning

confidence: 86%

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating

et al. 2021

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“…Exercise in the heat increases circulating S100β indicating that heat stress may alter blood-brain permeability (Watson et al, 2005). However, additional work refutes these findings during exercise in the heat (Cheuvront et al, 2008) and passive heat stress (Shepley et al, 2021) models in humans. Nonetheless, two recent studies in heatstroke patients demonstrated elevated S100β protein in the serum and cerebrospinal fluid of heatstroke patients (Chun et al, 2019;Li et al, 2020), with one study finding that the heatstroke patients with poor prognosis (defined as not being able to live without assistance at hospital discharge) having serum S100β concentrations ∼5 times higher than in heatstroke patients with a good prognosis (Chun et al, 2019).…”

Section: Brainmentioning

confidence: 87%

Biomarkers of heatstroke‐induced organ injury and repair

Schlader

Davis

Bouchama

2022

Experimental Physiology

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New Findings What is the topic of this review?The status and potential role of novel biological markers (biomarkers) that can help identify the patients at risk of organ injury or long‐term complications following heatstroke. What advances does it highlight?Numerous biomarkers were identified related to many aspects of generalized heatstroke‐induced cellular injury and tissue damage, and heatstroke‐provoked cardiovascular, renal, cerebral, intestinal and skeletal muscle injury. No novel biomarkers were identified for liver or lung injury. Abstract Classic and exertional heatstroke cause acute injury and damage across numerous organ systems. Moreover, heatstroke survivors may sustain long‐term neurological, cardiovascular and renal complications with a persistent risk of death. In this context, biomarkers, defined as biological samples obtained from heatstroke patients, are needed to detect early organ injury, and predict outcomes to develop novel organ preservation therapeutic strategies. This narrative review provides preliminary insights that will guide the development and future utilization of these biomarkers. To this end, we have identified numerous biomarkers of widespread heatstroke‐associated cellular injury, tissue damage and repair (extracellular heat shock proteins 72 and 60, high mobility group box protein 1, histone H3, and interleukin‐1α), and other organ‐specific biomarkers including those related to the cardiovascular system (cardiac troponin I, endothelium‐derived factors, circulation endothelial cells, adhesion molecules, thrombomodulin and von Willebrand factor antigen), the kidneys (plasma and urinary neutrophil gelatinase‐associated lipocalin), the intestines (intestinal fatty acid‐binding protein 2), the brain (serum S100β and neuron‐specific enolase) and skeletal muscle (creatine kinase, myoglobin). No specific biomarkers have been identified so far for liver or lung injury in heatstroke. Before translating the identified biomarkers into clinical practice, additional preclinical and clinical prospective studies are required to further understand their clinical utility, particularly for the biomarkers related to long‐term post‐heatstroke health outcomes.

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“…(2020) and Shepley et al. (2021), arterial endothelium‐derived microvesicles at baseline and hyperthermia from the study by Bain et al. (2017) and related descriptive data (e.g.…”

Section: Methodsmentioning

confidence: 99%

“…The data presented were collected from a larger study involving investigations into cerebral metabolism (Bain et al, 2020) and blood-brain barrier permeability (Shepley et al, 2021), in addition to arterial endotheliumand platelet-derived microvesicles in hyperthermia (Bain et al, 2017). The present study encompasses a separate a priori hypothesis, where the only data overlap is the CBF measurements in the subset of participants from the studies by Bain et al (2020) and Shepley et al (2021), arterial endothelium-derived microvesicles at baseline and hyperthermia from the study by Bain et al (2017) and related descriptive data (e.g. core temperature).…”

Section: Participantsmentioning

confidence: 99%

Cerebral uptake of microvesicles occurs in normocapnic but not hypocapnic passive hyperthermia in young healthy male adults

Parikh,

Shepley,

Tymko

et al. 2023

The Journal of Physiology

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Passive hyperthermia causes cerebral hypoperfusion primarily from heat‐induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro‐inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water‐perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet‐poor plasma via cells expressing CD62E (activated endothelial cells), CD31+/CD42b− (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan‐leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P‐values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+/CD42b− (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2/pH‐mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. imageKey points The hyperthermia‐induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow. We tested the hypothesis that the respiratory‐induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow. At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross‐brain microvesicle kinetics. However, when core temperature was increased by 2°C with CO2/pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2/pH‐mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia. These new findings suggest that the heat‐induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain.

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Negligible influence of moderate to severe hyperthermia on blood-brain barrier permeability and neuronal parenchymal integrity in healthy men

Cited by 7 publications

References 66 publications

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating

Biomarkers of heatstroke‐induced organ injury and repair

Cerebral uptake of microvesicles occurs in normocapnic but not hypocapnic passive hyperthermia in young healthy male adults

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