**Conflict of interest**

The only effective pharmacological therapy of acute ischemic stroke in humans is thrombolysis with recombinant tissue plasminogen activator, but DM is sometimes an exclusion criterion in recurrent stroke treatment. The time window for the therapy is narrow, and no other pharmacological agents have demonstrated efficacy in improving outcomes after ischemic stroke [1–4, 100, 102]. Thus, the searches for alternative approaches are welcomed. HBO [113] improves oxygen delivery and postischemic metabolism, restores ion pump function, and allows time for collateral circulation to develop [107]. In normal tissue, it causes vasoconstriction, but in ischemic brain tissue, it increases microvascular flow and improves oxygen dissolution and transport [109]. Time window for HBO application may be up to 6 hours [108], which is longer than the time window for thrombolytic therapy. HBO raises oxygenation of ischemic penumbra by 20% and improves mitochondrial function [107, 108]. It has anti-inflammatory effect by reducing expression of cyclooxygenase-2 and reduces the number of intercellular adhesion molecules and therefore reduces adhesion and infiltration of leukocytes [24]. However, guidelines do not recommend HBO treatment for acute ischemic stroke due to somewhat inconclusive data [102]. Some data imply that the intervention may be harmful causing middle ear trauma, epileptic seizures, and claustrophobia, while others found no firm evidence that HBO improves clinical outcomes for acute stroke. However, the main disadvantage of these trials used in meta-analysis was delay from stroke onset to initia-

98 Hyperbaric Oxygen Treatment in Research and Clinical Practice - Mechanisms of Action in Focus

tion of HBO and the need for care delivery in a specialized chamber [114].

prolonged ischemia and applied HBO treatment too late after stroke.

side of clinical trials (except caused by air embolism).

**8. Conclusion**

To conclude, HBO is currently not recommended for patients with acute ischemic stroke out-

On the other hand, some preclinical experiments suggest that if administered shortly after the stroke, HBO is highly effective treatment of stroke in diabetic female rats, even in the presence of long-term untreated DM [109]. Experiments that did not show effectiveness of HBO were possibly unsuccessful due to the unrecognizing the vulnerability of neurons. They used

The mechanisms by which HBO exerts its potentially beneficial effects are not completely clear. They cannot be simply explained as a consequence of supplementation of the oxygen deficit in certain conditions where oxygen is lacking, but it was demonstrated that HBO affects signaling cascades in cells and has multiple interacting complex mechanisms that might contribute to functional changes of blood vessels. Interactions of mechanisms affecting endothelial dysfunction, NO synthesis, EETs formation, CYP expression changes, oxidative stress and antioxidant defense system changes, and multiple effects on inflammation take place that might be considered as mediating factors for the observed positive (or negative) clinical effects in diabetes mellitus (for instance in chronic diabetic wounds). Studies on vasculature in diabetic animal models can provide us with more information that can help us understand its effects on blood vessel function, and **Table 1** summarizes the most relevant mechanisms that have been described in this text regarding functional vascular changes in The authors have no conflict of interest to declare.

## **Author details**

Ivana Jukic1 , Mihael Mišir1,2, Martina Mihalj1 , Zrinka Mihaljevic1 , Sanela Unfirer1,3, Dijana Kibel1,4 and Aleksandar Kibel1,5\*

\*Address all correspondence to: aleksandar\_mf@yahoo.com

1 Department of Physiology and Immunology, Faculty of Medicine, University of Osijek, Osijek, Croatia

2 Neurological Clinic, Osijek University Hospital, Osijek, Croatia

3 Emergency Department, Osijek University Hospital, Osijek, Croatia

4 Department of Diagnostic and Interventional Radiology, Osijek University Hospital, Osijek, Croatia

5 Department for Heart and Vascular Diseases, Osijek University Hospital, Osijek, Croatia
