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Ischemic cerebrovascular disease (ICD), the most common neurological disease worldwide, can be classified based on the onset time (acute/chronic) and the type of cerebral blood vessel involved (artery or venous sinus). Classifications include acute ischemic stroke (AIS)/transient ischemic attack (TIA), chronic cerebral circulation insufficiency (CCCI), acute cerebral venous sinus thrombosis (CVST), and chronic cerebrospinal venous insufficiency (CCSVI). The pathogenesis of cerebral arterial ischemia may be correlated with cerebral venous ischemia through decreased cerebral perfusion. The core treatment goals for both arterial and venous ICDs include perfusion recovery, reduction of cerebral ischemic injury, and preservation of the neuronal integrity of the involved region as soon as possible; however, therapy based on the current guidelines for either acute ischemic events or chronic cerebral ischemia is not ideal because the recurrence rate of AIS or CVST is still very high.
- remote ischemic conditioning (RIC)
- normobaric hyperoxia (NBO)
- hypothermia
- batroxobin
- ischemic cerebrovascular disease
1. Introduction
Ischemic cerebrovascular disease (ICD) is the pathological process in which an area of the brain is temporarily or permanently affected by ischemia involving one or more cerebral blood vessels. ICD can develop from a variety of causes [1,2,3]. Despite the lack of consensus, ICD is often classified according to the onset time (acute/chronic) and the type of cerebral blood vessel involved (artery or venous sinus). Therefore, classifications include acute ischemic stroke (AIS)/transient ischemic attack (TIA) [4,5], chronic cerebral circulation insufficiency (CCCI), acute cerebral venous sinus thrombosis (CVST), and chronic cerebrospinal venous insufficiency (CCSVI) [1,2,3,6]. In clinical settings, cerebral arterial and cerebral venous ischemia are typically regarded as separate pathological processes due to different etiologies. Therefore, each has different traditional treatment methods [7]. However, the pathogenesis of cerebral arterial ischemia may be correlated to cerebral venous ischemia since both forms of ischemia can reduce cerebral perfusion [6,8]. Therefore, from a broader perspective, it is apparent that the core treatment goals for both arterial and venous ICD are cerebral perfusion recovery, ischemic injury reduction, and preservation of the neuronal integrity in the affected ischemic region as soon as possible [9].
Long-term CCCI due to large vessel stenosis, atherosclerotic stenosis, or the occlusion of the intracranial and extracranial large arteries is the initiating factor of cerebral arterial ischemia, which leads to AIS or TIA [10]. In appropriate patients, AIS treatment involves tissue plasminogen activator (tPA)/tenecteplase (TNK) fibrinolysis (within 4.5 h from onset) or thrombectomy. CCCI treatments, such as the standardized use of anti-platelet, hypertension, hyperlipidemia, and type 2 diabetes medications, mainly focus on the secondary prevention of an aggressive atherosclerosis formation [11]. However, even after such treatments, the incidence of CCCI/AIS and the recurrence rate of AIS are still very high, ranging from 5.7% to 51.3% [12,13].
Treatment of ischemia in the cerebral venous sinus or cortical veins is limited to anti-coagulation for the long-term management of chronic CVST or thrombectomy in acute CVST. CCSVI due to chronic CVST, cerebral cortical vein thrombosis (CCVT), enlarged arachnoid granules, and the compression of bones is challenging to treat due to the low anticoagulant concentration in chronic venous thrombosis or small cerebral cortical veins, as well as limited options for surgical correction [14].
Novel pharmaceutical and non-pharmaceutical methods for recovering cerebral perfusion and neuroprotection are highly sought. Although some drugs were promising in preclinical models for improving cerebral perfusion and rescuing ischemic areas, their use has not translated to clinical settings due to the failure to include stroke models with significant comorbidities and a lack of testing in older animal models [9,15,16]. Still, several clinical trials have yielded positive results and indicated beneficial effects in stroke patients, such as the use of human urinary kallidinogenase (HUK) (NCT03431909 Phase IV China), edaravone (NCT02430350 Phase III China/Japan), and nerinetide (NA-1) (NCT02930018 Phase III Canada and USA) [17]. Most intriguingly, in multiple clinical trials, batroxobin has recently drawn attention due to its protective effects in the cerebral artery and venous ischemia [18,19,20]. Non-pharmaceutical neuroprotective methods, including normobaric oxygen therapy (NBO), remote ischemic conditioning (RIC), and hypothermia, have been tested in several clinical trials, and the beneficial effects remain controversial for stroke prevention and recurrence [21,22,23].
2. Batroxobin
Batroxobin, isolated from Bothrops atrox moojeni snake venom, is widely used in treating AIS and CVST due to its role in promoting thrombolysis, recurrence of thrombus, and neuroprotection. Batroxobin could be an effective adjunctive therapy to traditional anti-coagulation and anti-platelet treatments due to its proven safety and low incidence of hemorrhage transformation in multiple preliminary clinical studies [14,19,20,24,25]. Previously, our team systematically summarized the clinical effects and related mechanisms of batroxobin in various vascular diseases [18] Therefore, this review focuses on the protective effects and mechanisms of batroxobin in ICD.
2.1. Possible Neuroprotective Mechanisms of Batroxobin
In animal models of cerebral ischemia or ischemia-reperfusion, batroxobin was involved in the inhibition of neuron apoptosis, reduction of cerebral edema, a decrease in hemorrhagic transformation, and the recovery of cerebral perfusion to the infarcted sites [18]. Several pathophysiological mechanisms based on preclinical studies were proposed regarding the neuroprotective effects of batroxobin. First, batroxobin directly targets fibrinogen, a significant component of clots; therefore, batroxobin could decrease the deposition of fibrinogen to form fibrin [26,27,28,29]. Another neuroprotective effect of batroxobin was the direct up-regulation of myelin basic protein (MBP), which is vital in nerve myelination in the nervous system [27]. Moreover, batroxobin activates endothelial cells to release endogenous tPA, promoting thrombolysis. Batroxobin could also increase the bioactivity of superoxide dismutase (SOD) and eliminate oxygen-free damage to the infarcted area [18]. Lastly, batroxobin may inhibit the expression of various pro-inflammatory markers in peripheral serum and the injured cerebral region (e.g., serum tumor necrosis factor-alpha (TNF-α), heat shock proteins 32 and 70 in the cerebral ischemic region, and complements C3d and C9 in the cerebral perihematomal area) [30,31,32].
Batroxobin, as an adjunctive therapy was more widely tested in patients with AIS [24,33,34,35,36,37,38,39], and more recently, a few clinical studies extended the application of batroxobin in CCCI [25] and CVST [19,20]. Most clinical studies have shown positive effects in prognosis after batroxobin usage; however, these studies are limited to small sample sizes, population selection biases (most studies are based in Asian countries), unblinding and unrandomized procedures, and various treatment regimens between different studies. Therefore, interpretations of the findings should be made with caution.
2.2. Batroxobin and AIS
Several clinical studies evaluated the efficacy and safety of different treatment regimens of batroxobin in AIS patients [24,33,34,35,36,37,38,39]. The use of batroxobin alone decreased fibrinogen concentrations and erythrocyte aggregability, reduced stroke recurrence rates, and produced more significant improvements in neurological assessments [18]. Interestingly, AIS/TIA patients with hyperfibrinogenemia saw a more substantial benefit when using batroxobin than that with normal serum fibrinogen levels, perhaps due to the elimination of excessive fibrinogen [38]. Moreover, the combined use of batroxobin and the standard post-stroke treatment (aspirin and statins) proved safe in several clinical studies and improved cerebral hemodynamics [33,39,40].
The combined use of edaravone and batroxobin was also evaluated in several small-size randomized case–control studies in the Chinese population, including two studies that enrolled patients with progressive AIS [24,35,37]. Although the exact mechanism of action in the edaravone treatment of AIS is unknown, its therapeutic effect may be due to its known antioxidant properties [17]. Post-stroke oxidative stress is a part of the process that damages the infarcted area. Wu et al. observed decreased neurological deficit scores and serum fibrinogen levels in AIS patients treated with either batroxobin alone or in combination with edaravone, with no adverse effects in either group. Further, the combination group had a higher effective rate than the group that received only batroxobin [24]. Ren et al. and Wang et al. included patients with progressive AIS [35,37]. Similar results with Wu et al. were also founded. However, these results should be interpreted with caution due to the limited sample size and variable treatment duration (30 mg intravenous edaravone for 10 days or 30 mg intravenous edaravone for 14 days). Evaluating the safety and efficacy of batroxobin in more extensive randomized clinical trials is necessary.
2.3. Batroxobin and CCCI
Unlike AIS, CCCI exhibits a chronic degenerative course in the absence of acute symptoms, leading to a delayed diagnosis in many patients [10]. Without treatment or intervention, CCCI can lead to adverse events such as cognitive impairment, depression, and AIS. Due to a lack of effective treatments or drugs, CCCI treatment is limited to diet and physical activity modification and pharmaceutically controlling the risk factors of hyperlipidemia, high blood pressure, or diabetes mellitus [3]. Zhai et al. evaluated the effects of batroxobin in patients with vascular cognitive dysfunction. Compared to the control group (standardized use of aspirin only), patients who received a combination of aspirin and batroxobin displayed a considerable improvement in cognitive function and quality of daily life [25].
3. Normobaric Oxygen
3.1. Possible Neuroprotective Mechanisms of NBO
Oxygen supplementation is a common adjuvant therapy for various diseases. Based on the inhaled oxygen pressure (greater than or equal to atmospheric pressure, 1 ATM = 101.325 kPa), oxygen therapy can be classified into NBO and hyperbaric oxygen (HBO) [45]. HBO is not widely used due to the expensive cost of implementation and its potentially damaging side effects on lung tissues. However, the neuroprotective role of NBO (given via facial mask or nasal cannula) has been suggested in treating strokes, as it is non-invasive and easy to administer in prehospital settings. Despite there being no significant increase of the total arterial oxygen content, NBO safely and effectively increased the ischemic penumbral partial pressure of oxygen (PtO2) in various rodent models of ischemic stroke [46]. Moreover, NBO treatment did not cause oxidative stress, which is common in theory after reperfusion [47].
3.2. NBO and AIS
Our team previously performed a meta-analysis to evaluate the effect of NBO in AIS patients based on eleven prospective RCT studies and found that existing data trended toward treatment-related benefits, which was encouraging for researchers in this field [43]. The promising value of NBO needed further examination based on standard modes of NBO intervention. Most studies concluded that NBO intervention initiated within 12 h of stroke onset resulted in a better prognosis. Oxygen flow velocity in these studies was usually set as 10 L/min and maintained for more than 12 h. A systematic review by Mahood et al., which included fifteen articles on NBO therapy for AIS patients, comprehensively reviewed the outcomes of mortality, symptom relief, neurological function, and neuroimaging improvements in AIS patients after NBO intervention [48]. Although the difference between the NBO group and the control group was not considered significant due to the small sample size and heterogeneity of NBO intervention modes, the authors observed a neuroprotective trend associated with NBO treatment. No oxygen-related adverse events were reported, and the incidence of serious adverse events was lower in the NBO group.
3.3. NBO and CCCI
Considering the shared underlying mechanisms between the penumbra during a stroke and the ischemic–hypoxic brain tissues in CCCI, we speculate that NBO may be a promising therapeutic strategy for attenuating short-term symptoms or improving long-term clinical outcomes among CCCI patients [44]. However, few studies have evaluated the efficacy of NBO in CCCI patients. Our team was the first to test the neuroprotective effects of NBO in CCCI. Additionally, Ding et al. innovatively utilized EEG recordings to detect early changes in CCCI-related EEG anomalies more precisely after NBO [49]. Further, NBO ameliorates CCCI-related EEG anomalies, including attenuating abnormal high-power oscillations and the slow paroxysmal activities associated with CCCI. A more precise method of detection, such as EEG, may be helpful in the evaluation of NBO efficacy. Experimental and clinical studies are necessary to shed more light on the application of NBO in CCCI.
4. Remote Ischemic Conditioning (RIC)
RIC is the application of reversible episodes of ischemia and reperfusion in one vascular bed, tissue, or organ, conferring global protection and rendering remote tissues and organs resistant to ischemia/reperfusion injury. Upper limb RIC has mainly been applied in clinical trials. In its first description by Murry et al. in 1986, RIC was viewed as a promising cardioprotective technique [50]. The CONDI-1 trial (n = 333) [51], RIC-STEMI trial (n = 258) [52], and LIPSIA CONDITIONING study (n = 696) [53] provided evidence that RIC could reduce circulating biomarkers of myocardial necrosis and edema and could improve cardiac function. Recently, the role of RIC in improving STEMI patient prognosis has been questioned mainly due to the nonbeneficial effects of RIC illustrated by Derek et al. in the CONDI-2/ERIC-PPCI trial, a large and appropriately powered randomized controlled trial (n = 5401) [22,54,55]. However, RIC has been gradually used for post-stroke rehabilitation and prevention of recurrence due to its proven beneficial effect in randomized clinical trials (though with a small sample size of fewer than 100 patients) and user-friendly design (easy to carry on, non-invasive, and cost-effective) [56,57]. Several previous reviews have demonstrated the protective mechanisms in ICD based on the interaction of neural, humoral, and immunological systems induced by RIC [10,58].
This entry is adapted from the peer-reviewed paper 10.3390/jcm11206193
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