Remote but not Distant: a Review on Experimental Models and Clinical Trials in Remote Ischemic Conditioning as Potential Therapy in Ischemic Stroke

Abstract

Stroke is one of the main causes of neurological disability worldwide and the second cause of death in people over 65 years old, resulting in great economic and social burden. Ischemic stroke accounts for 85% of total cases, and the approved therapies are based on re-establishment of blood flow, and do not directly target brain parenchyma. Thus, novel therapies are urgently needed. In this review, limb remote ischemic conditioning (RIC) is revised and discussed as a potential therapy against ischemic stroke. The review targets both (i) fundamental research based on experimental models and (ii) clinical research based on clinical trials and human interventional studies with healthy volunteers. Moreover, it also presents two approaches concerning RIC mechanisms in stroke: (i) description of the underlying cerebral cellular and molecular mechanisms triggered by limb RIC that promote neuroprotection against stroke induced damage and (ii) the identification of signaling factors involved in inter-organ communication following RIC procedure. Limb to brain remote signaling can occur via circulating biochemical factors, immune cells, and/or stimulation of autonomic nervous system. In this review, these three hypotheses are explored in both humans and experimental models. Finally, the challenges involved in translating experimentally generated scientific knowledge to a clinical setting are also discussed.

Keywords: Hormesis; Ischemic stroke; Neuroinflammation; Neuroprotection; Oxidative stress; Remote ischemic conditioning.

Fig. 1

Limb remote ischemic conditioning (RIC) and neuroprotection.Scheme for RIC applied in the arm and the potential signaling that confers neuroprotection

Fig. 2

Timing for ischemic conditioning.There are three different times for the application of ischemic conditioning in the context of ischemic stroke: pre-conditioning (before ischemia), per-conditioning (after ischemia before reperfusion), and post-conditioning (after the onset of reperfusion)

Fig. 3

Chronological cellular and molecular consequences of ischemic stroke and the associated processes involved in neuroprotection.Following ischemic stroke, there is rapid generation of excitotoxicity, necrosis, oxidative, and nitrosative stress in the core of stroke. Later on (hours up to few days), there is apoptosis, neuroinflammation, bioenergy catastrophe, BBB permeabilization, and still oxidative and nitrosative stress, which are more associated with penumbra area of stroke

Fig. 4

Rationale of the review.Organization of data generated by experimental models or human-based studies (including clinical trials). Data were divided in two: description of the underlying cerebral cellular and molecular mechanisms triggered by limb RIC that promote neuroprotection against stroke-induced damage and the identification of signaling factors involved in inter-organ communication following RIC procedure

Fig. 5

A Pathways and gene expression that are altered by limb pre-RIC following ischemic stroke and that are related to neuroprotection in experimental models.There is a timeline with the altered pathways and gene expression that occurs when limb RIC is applied before the ischemic stroke (pre-RIC) in comparison with ischemic stroke without RIC. When pre-RIC is induced up to 1h before ischemic stroke, the altered events are represented in the upper part of the figure. In the lower part of the figure, there are the events occurring when pre-RIC is induced between 1h and 3 days before ischemic stroke. In the right hand side, the required conditions for pre-RIC to protect the brain against ischemic stroke are described. The altered pathways and different gene expressions are described accordingly with brain region that is represented by different colors. The reference number is described in Tables 1 and 2. The used symbols are for upregulated/increased and for downregulated/reduced. B Pathways and gene expression that are altered by limb per- and post-RIC following ischemic stroke and that are related to neuroprotection in experimental models.There is a timeline with the altered pathways and gene expression that occurs when limb RIC is applied after the ischemic insult before reperfusion (per-RIC) and after ischemia and reperfusion up to 1h (rapid post-RIC) or at later stages (post-RIC). In all three cases, alterations in pathways and gene expression are compared with ischemic stroke without RIC treatment. In the right hand side, the required conditions for per- and post-RIC to protect the brain against ischemic stroke are described. The altered pathways and different gene expressions are described accordingly with brain region that is represented by different colors. The reference number is described in Tables 1 and 2. The used symbols are for upregulated/increased and for downregulated/reduced

Fig. 5

A Pathways and gene expression that are altered by limb pre-RIC following ischemic stroke and that are related to neuroprotection in experimental models.There is a timeline with the altered pathways and gene expression that occurs when limb RIC is applied before the ischemic stroke (pre-RIC) in comparison with ischemic stroke without RIC. When pre-RIC is induced up to 1h before ischemic stroke, the altered events are represented in the upper part of the figure. In the lower part of the figure, there are the events occurring when pre-RIC is induced between 1h and 3 days before ischemic stroke. In the right hand side, the required conditions for pre-RIC to protect the brain against ischemic stroke are described. The altered pathways and different gene expressions are described accordingly with brain region that is represented by different colors. The reference number is described in Tables 1 and 2. The used symbols are for upregulated/increased and for downregulated/reduced. B Pathways and gene expression that are altered by limb per- and post-RIC following ischemic stroke and that are related to neuroprotection in experimental models.There is a timeline with the altered pathways and gene expression that occurs when limb RIC is applied after the ischemic insult before reperfusion (per-RIC) and after ischemia and reperfusion up to 1h (rapid post-RIC) or at later stages (post-RIC). In all three cases, alterations in pathways and gene expression are compared with ischemic stroke without RIC treatment. In the right hand side, the required conditions for per- and post-RIC to protect the brain against ischemic stroke are described. The altered pathways and different gene expressions are described accordingly with brain region that is represented by different colors. The reference number is described in Tables 1 and 2. The used symbols are for upregulated/increased and for downregulated/reduced