Human Umbilical Cord Therapy Improves Long-Term Behavioral Outcomes Following Neonatal Hypoxic Ischemic Brain Injury

Background: Hypoxic ischemic (HI) insult in term babies at labor or birth can cause long-term neurodevelopmental disorders, including cerebral palsy (CP). The current standard treatment for term infants with hypoxic ischemic encephalopathy (HIE) is hypothermia. Because hypothermia is only partially effective, novel therapies are required to improve outcomes further. Human umbilical cord blood cells (UCB) are a rich source of stem and progenitor cells making them a potential treatment for neonatal HI brain injury. Recent clinical trials have shown that UCB therapy is a safe and efficacious treatment for confirmed cerebral palsy. In this study, we assessed whether early administration of UCB to the neonate could improve long-term behavioral outcomes and promote brain repair following neonatal HI brain injury.Methods: HI brain injury was induced in postnatal day (PND) 7 rat pups via permanent ligation of the left carotid artery, followed by a 90 min hypoxic challenge. UCB was administered intraperitoneally on PND 8. Behavioral tests, including negative geotaxis, forelimb preference and open field test, were performed on PND 14, 30, and 50, following brains were collected for assessment of neuropathology.Results: Neonatal HI resulted in decreased brain weight, cerebral tissue loss and apoptosis in the somatosensory cortex, as well as compromised behavioral outcomes. UCB administration following HI improved short and long-term behavioral outcomes but did not reduce long-term histological evidence of brain injury compared to HI alone. In addition, UCB following HI increased microglia activation in the somatosensory cortex compared to HI alone.Conclusion: Administration of a single dose of UCB cells 24 h after HI injury improves behavior, however, a single dose of cells does not modulate pathological evidence of long-term brain injury

Persistent Inflammation in Cerebral Palsy: Pathogenic Mediator or Comorbidity? A Scoping Review

Research has established inflammation in the pathogenesis of brain injury and the risk of developing cerebral palsy (CP). However, it is unclear if inflammation is solely pathogenic and primarily contributes to the acute phase of injury, or if inflammation persists with consequence in CP and may therefore be considered a comorbidity. We conducted a scoping review to identify studies that analyzed inflammatory biomarkers in CP and discuss the role of inflammation in the pathogenesis of CP and/or as a comorbidity. Twelve included studies reported a range of analytes, methods and biomarkers, including indicators of inflammatory status, immune function and genetic changes. The majority of controlled studies concluded that one or more systemic biomarkers of inflammation were significantly different in CP versus controls; most commonly serum or plasma cytokines such as tumor necrosis factor, Interleukin (IL)-6 and IL-10. In addition, differences in inflammation were noted in distinct subgroups of CP (e.g., those with varying severity). The available evidence supports the pathogenic role of inflammation and its ongoing role as a comorbidity of CP. This review shows that inflammation may persist for decades, driving functional impairment across development and into adulthood. However, inflammation is complex, thus further research will increase our understanding

Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy

Cell therapies are an emergent treatment for cerebral palsy (CP) with promising evidence demonstrating efficacy for improving gross motor function. However, families value improvements in a range of domains following intervention and the non-motor symptoms, comorbidities and complications of CP can potentially be targeted by cell therapies. We conducted a scoping review to describe all outcomes that have been reported in cell therapy studies for CP to date, and to examine what instruments were used to capture these. Through a systematic search we identified 54 studies comprising 2066 participants that were treated with a range of cell therapy interventions. We categorized the reported 53 unique outcome instruments and additional descriptive measures into 10 categories and 12 sub-categories. Movement and Posture was the most frequently reported outcome category, followed by Safety, however Quality of Life, and various prevalent comorbidities and complications of CP were infrequently reported. Notably, many outcome instruments used do not have evaluative properties and thus are not suitable for measuring change following intervention. We provide a number of recommendations to ensure that future trials generate high-quality outcome data that is aligned with the priorities of the CP community

Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats

(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic–ischaemic (HI)-induced injury. (2) Methods: To induce HI injury, postnatal day (PND) 10 rat pups underwent single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). Pups received daily tacrolimus (or a vehicle) starting either 3 days before HI on PND 7 (pre-HI), or 12 h after HI (post-HI). Four doses were tested: 0.025, 0.05, 0.1 or 0.25 mg/kg/day. Pups were euthanised at PND 17 or PND 50. (3) Results: All tacrolimus doses administered pre-HI significantly reduced brain infarct size and neuronal loss, increased the number of resting microglia and reduced cellular apoptosis (p p < 0.05). All doses of tacrolimus reduced pup weight compared to the controls. (4) Conclusions: Tacrolimus administration 3 days pre-HI was neuroprotective, likely mediated through neuroinflammatory and cell death pathways. Tacrolimus post-HI may have limited capacity to reduce brain injury, with higher doses increasing rat pup mortality. This work highlights the benefits of targeting neuroinflammation during the acute injurious period. More specific targeting of neuroinflammation, e.g., via T-cells, warrants further investigation

Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic–Ischemic Brain Injury

Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic&#8722;ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury