The Current Status Of Neuroprotection in Congenital Heart Disease Part 3

Although developments in the understanding of minocycline's neuroprotective capacity suggest potential applications for attenuation of neurologic injury, it should be remembered that in neonates, tetracycline can cause stunting of bone growth and bilirubin-induced brain damage [119].5.4. Triptolide.

In recent years, more and more studies have shown that minocycline plays a very important role in neuroprotection and memory. Minocycline is a broad-spectrum antibiotic that was initially used to treat bacterial infections, but it was only later that its broader effects began to be discovered, particularly in the neurological field.

Research has found that minocycline can protect the brain by suppressing inflammation and reducing neuronal loss. This means that minocycline may have a good therapeutic effect on some neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.

What's more, there are also studies showing that minocycline may help enhance cognitive function and improve memory. In animal experiments, mice treated with minocycline had better learning and memory abilities than mice that were not treated. In addition, minocycline is thought to improve memory by affecting synaptic plasticity, promoting neurogenesis, and improving the neural environment.

However, although minocycline has certain potential in neuroprotection and memory, we also need to note that it may produce some side effects in some people, such as headache, dizziness, nausea, etc. Therefore, we should consult a doctor and follow the doctor's advice before using minocycline.

In general, minocycline, as a broad-spectrum antibiotic, has received increasing attention for its application in the neurological field. Although its role still needs further research and understanding, we are full of expectations for its potential in neuroprotection and memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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Triptolide is an extract of Tripterygium wilfordii, a plant commonly used in traditional Chinese medicine [111]. Known for its anti-inflammatory and immunosuppressive activity, Triptolide is a prospective therapeutic for addressing upregulated inflammatory pathways associated with CPB. 

Previous in vitro studies modeling traumatic brain injury, cerebral ischemia/reperfusion injury, and stroke have confirmed the presence of anti-inflammatory effects driven by suppressed activation of the NF-kB and p38MAPK pathways [112–114]. Importantly, these studies showed attenuated neurological deficits to be associated with Triptolide treatment [113]. 

A more recent experimental study applied these results to a 12–14 week rat model of CPB with DHCA and concluded that Triptolide treatment led to decreased levels of TNF a, IL1b, IL6, malondialdehyde, and ROS while increasing glutathione and superoxide dismutase levels [115]. Moreover mitigated microglia activation, NF-kB activity inhibition, and upregulation of the NRF2 pathway were observed, further emphasizing Triptolide's anti-inflammatory and neuroprotective qualities. 

Neurodevelopmental endpoints in the same study were found to be positively impacted by Triptolide administration evident in improved spatial learning, memory, and anxiety-like behaviors. Given that the model used in this study was an adult rat, the results should be interpreted carefully for neonates. Further study in a neonate model is needed.

5.5. Minocycline

Minocycline is a tetracycline antibiotic commonly used for chronic recurrent bacterial infections [116]. Lately, its anti-inflammatory and neuroprotective properties have been highlighted in several animal models. Drabek et al. showed in their rat model that minocycline significantly attenuated brain tumor necrosis factor-alpha, a principal mediator of neuroinflammation after CPB followed by DHCA [117]. Aida et al. demonstrated significant attenuation of markers for hypoxia and apoptosis in cells from the hippocampus of 4-week-old piglets with 90 min of CPB followed by minocycline administration [118]. Results from these animal studies may provide sufficient rationale to perform clinical.

6. Post-Operative Neuroprotection-Clinical Studies

6.1. Triiodothyronine

Thyroid hormones are a critical component of neurodevelopment in the post-natal period. In particular, the processes of cerebellar neurogenesis, gliogenesis, and myelogenesis rely on adequate Triiodothyronine levels while hypothyroxinemia has been observed to be associated with developmental delay [120]. Even transient congenital hypothyroidism in neonates has been reported to be associated with lower IQ at 7–8 years of age [121]. 

Reductions in thyroid hormone levels have been reported postoperatively after pediatric and adult cardiac surgery [122,123]. Bettendorf et al. attempted to raise thyroid levels in a cohort of 40 children undergoing cardiac surgery with triiodothyronine treatment and were able to verify that triiodothyronine is efficacious in elevating triiodothyronine plasma levels while improving myocardial function and reducing postoperative intensive care [124]. 

The long-term neuroprotective effects of triiodothyronine supplementation were assessed for the first time in the same cohort 10 years later. In the follow-up study, no significant differences were observed in IQ, gross and fine motor skills, and executive function between the triiodothyronine-treated and control groups [125].

6.2. Standardized Exercise Program

The numerous benefits of physical activity are well established [126]. Importantly the impact of physical activity has also been shown to extend to aspects of cognition and neurodevelopment. Several studies in adults have demonstrated evidence suggestive of relationships between physical activity and hippocampal volume preservation as well as increased brain volume [127–130]. 

One randomized control trial even demonstrated a 2% increase in hippocampal volume corresponding to better spatial memory in response to a physical activity regimen [131]. In preadolescent children, improved executive function, attention, and academic performance have also been found to be associated with physical activity [132]. Similar results have been reported in CHD. Dulfer et al. randomized patients 10 to 25 years old with Tetralogy of Fallot or single ventricle anomalies into a 3-month standardized exercise program [133].

Aside from demonstrating better quality-of-life measures in the exercise group, the authors also observed positive effects in self-reported cognitive functioning and parent-reported social functioning. In addition, an ongoing clinical trial at Columbia University will attempt to show similar findings in a younger patient group through IQ, cognitive function, and adaptive behavior evaluations at 24 months (https://clinicaltrials.gov/ct2/show/NCT02542683, accessed on 3 November 2021).

6.3. Physical Therapy

The effects of physical therapy in the context of CHD have been rarely described. However, an observational cohort study in 2021 looking at gross motor development in children with CHD found increased Bayley-III scores during 12–24 month up assessments in patients who received regular physical therapy compared to those who received either no physical therapy or occasional physical therapy [134]. A recent study reported that the majority of a CHD cohort did not meet guidelines for physical fitness and had not received physical therapy 2 years postoperatively. Further investigation should be conducted to determine if participation in physical therapy by patients with CHD will promote motor skill development [135].

6.4. Cogmed Working Memory Training

The Cogmed Working Memory Training is a 5-week computerized program designed to enhance executive function, organization, and attention [136]. While its use has been shown to impart these benefits in children and adolescents with ADHD, and learning disabilities as well as those who were born pre-term, its effects have yet to be demonstrated in patients with CHD [137–139]. 

Recently a clinical trial studied the efficacy of Cogmed Working Memory Training in a group of 13–16-year-old adolescents. This trial specifically found that the training improved inhibitory control, attention, planning, and organizational skills immediately after training and at 3-month follow-up [136]. Furthermore, the group assigned to the training demonstrated higher social responsiveness and communication scores. 

Although components of working memory and processing speed did not improve as previously reported in other patient populations, the Cogmed Working Memory Training had an overall positive impact on the neurological function of adolescents with CHD. A trial recently completed in 2020 is anticipated to show similar improvements specifically in patients with CHD in the age range of 7–12 years https://clinicaltrials.gov/ct2/show/ NCT03023644, accessed on 3 November 2021).

6.5. Early Stimulation

The environment of the patient with CHD is crucial for their neurodevelopment. Among known non-biological factors such as maternal education and deprivation, a cognitively stimulating environment is known to be a modifiable factor with the capability to overcome other factors contributing to deficits in neurodevelopment [140–143]. Bonthrone et al. retrospectively assessed the level of cognitive stimulation of children with CHD by their parents and found that higher parent cognitive stimulation scores were associated with higher 22-month language and cognitive abilities [144]. 

A research group at the Instituto de Cardiologia de Rio Grande do Sul is investigating the effects of parent-administered early stimulation programs for children with CHD in a randomized prospective clinical trial by using 3 and 6-month neurodevelopmental scores as their primary endpoints (https://clinicaltrials.gov/ct2/show/NCT04152330, accessed on 3 November 2021).

7. Socioeconomic Status

We can't disregard and close this review without talking about socioeconomic status (SES). SES is a measure of one's overall status and position in society, which is a well-recognized predictor of neurodevelopmental outcomes in preterm children and may attenuate the effect of brain injury particularly on cognitive development [44]. Indeed, in many studies reporting shorter and longer-term neurodevelopmental outcomes, lower SES has been identified as an independent risk factor for worse outcomes in the CHD population [10,145–147]. Less maternal education has been associated with a lower mental development index in infants with CHD [148]. 

Thus, particular attention must be given to neurodevelopmental care during the hospitalization and after discharge in children from disadvantaged families. A recent study reporting the relationship between a stimulating home environment and cognitive abilities in toddlers with CHD showed no relationship between outcome scores and SES, clinical factors, or brain injury severity at 22 months [144] However, the sample size is relatively small and future studies assessing the impact of home environment stimulation with larger samples are required.

8. Concluding Remarks and Future Perspectives
Neurodevelopmental deficits are common and important sequelae of CHD that are highly complex with cumulative, multifactorial, and synergistic etiologies. An important current limitation is that many clinical trials undertaken in the CHD population are based on clinical trials in other populations or on preclinical studies that target different mechanisms of injury. 

Therefore, the signaling pathways of the possible mechanisms and physiological events in children with CHD are not fully understood. While current therapies are being developed, continued collaboration and effort are needed to elucidate and dictate future areas of potential neuroprotective therapy in all stages of patient care. In addition, genetic contributions are now becoming a very important topic [31,32]. Although there is a need for a better understanding of the impact of CHD-linked genes on brain development, the studies presented in this paper shed light on potential future therapeutic options.

Author Contributions: Conceptualization, K.K., R.A.J., and N.I.; writing-original draft preparation, K.K. and C.L.; writing-review and editing, R.A.J. and N.I.; supervision, R.A.J., and N.I. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by National Institutes of Health (NIH) grant R33 HL146394 (N.I., R.A.J.), R01HL139712 (N.I.), and R01HL146670 (N.I.), and by the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under Award No. W81XWH2010199 (N.I.). We are thankful for the vision and generosity of the Foglia and Hill families who supported our studies.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Acknowledgments: Images in Figure 3 were retrieved from BioRender templates.

Conflicts of Interest: The authors declare no conflict of interest.

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