Emerging neuroprotective interventions in periventricular leukomalacia - A systematic review of preclinical studies

Abiramalatha, Thangaraj; Ramaswamy, Viraraghavan Vadakkencherry; Ponnala, Andelsivj Kumar; Kallem, Venkat Reddy; Murkunde, Yogeshkumar; Punnoose, Alan M.; Aravindhan, Vivekanandhan; Pullattayil, Abdul K.; Amboiram, Prakash

doi:10.1080/13543784.2022.2040479

Cited by 9 publications

(5 citation statements)

References 187 publications

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“…Periventricular leukomalacia (PVL) characterized by diffuse demyelination in the white matter of periventricular region [ 1 ], is the most common form of white matter injury caused by maternal infection between 23 and 32 weeks of gestation, resulting in impairments in learning, memory, and cognition [ 2 , 3 ]. The mortality associated with PVL is high, with more than 50% of the surviving children developing cerebral palsy [ 4 ], including anxiety, inhibitory control and deficits of attention [ 5–7 ].…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: PSB0788 ameliorates maternal inflammation‐induced periventricular leukomalacia-like injury

Wang

et al. 2022

Bioengineered

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Studies have shown that periventricular leukomalacia (PVL) is a distinctive form of cerebral white matter injury that pertains to myelination disturbances. Maternal inflammation is a main cause of white matter injury. Intrauterine inflammation cellular will be propagated to the developing brain by the entire maternal–placental–fetal axis, and triggers neural immune injury. As a low-affinity receptor, adenosine A 2B receptor (A 2B AR) requires high concentrations of adenosine to be significantly activated in pathological conditions. We hypothesized that in the maternal inflammation‐induced PVL model, a selective A 2B AR antagonist PSB0788 had the potential to prevent the injury. In this work, a total of 18 SD pregnant rats were divided into three groups, and treated with intraperitoneal injection of phosphate buffered saline (PBS), lipopolysaccharide (LPS), or LPS+PSB0788. Placental infection was determined by H&E staining and the inflammatory condition was determined by ELISA. Change of MBP, NG2 and CC-1 in the brain of the rats’ offspring were detected by western blot and immunohistochemistry. Furthermore, LPS-induced maternal inflammation reduced the expression of MBP, which related to the decrease in the numbers of OPCs and mature oligodendrocytes in neonate rats. After treatment with PSB0788, the levels of MBP proteins increased in the rats’ offspring, improved the remyelination. In conclusion, our study shows that the selective A 2B AR antagonist PSB0788 plays an important role in promoting the normal development of OPCs in vivo by the maternal inflammation‐induced PVL model. Future studies will focus on the mechanism of PSB0788 in this model.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: PSB0788 ameliorates maternal inflammation‐induced periventricular leukomalacia-like injury

Wang

et al. 2022

Bioengineered

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“…As reviewed elsewhere [29], melatonin has been investigated as a potential treatment for various neonatal conditions, encompassing periventricular leukomalacia [162], hypoxicischemic injury [163], respiratory distress syndrome [164], and sepsis [165]. Given the challenges of recruiting pregnant women for medical research, utilizing lactating women and their neonates as a reprogramming strategy presents a feasible starting point.…”

Section: Pros and Consmentioning

confidence: 99%

Melatonin Use during Pregnancy and Lactation Complicated by Oxidative Stress: Focus on Offspring’s Cardiovascular–Kidney–Metabolic Health in Animal Models

Tain,

Hsu

2024

Antioxidants

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Cardiovascular–kidney–metabolic (CKM) syndrome has emerged as a major global public health concern, posing a substantial threat to human health. Early-life exposure to oxidative stress may heighten vulnerability to the developmental programming of adult diseases, encompassing various aspects of CKM syndrome. Conversely, the initiation of adverse programming processes can potentially be thwarted through early-life antioxidant interventions. Melatonin, originally recognized for its antioxidant properties, is an endogenous hormone with diverse biological functions. While melatonin has demonstrated benefits in addressing disorders linked to oxidative stress, there has been comparatively less focus on investigating its reprogramming effects on CKM syndrome. This review consolidates the current knowledge on the role of oxidative stress during pregnancy and lactation in inducing CKM traits in offspring, emphasizing the underlying mechanisms. The multifaceted role of melatonin in regulating oxidative stress, mediating fetal programming, and preventing adverse outcomes in offspring positions it as a promising reprogramming strategy. Currently, there is a lack of sufficient information in humans, and the available evidence primarily originates from animal studies. This opens up new avenues for novel preventive intervention in CKM syndrome.

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“…Preterm white matter injury (PWMI) affects approximately 20,000 neonates in the United States annually and can result in lifelong motor and cognitive disability [1][2][3] . There are no specific treatments available; symptom-directed supportive care is the mainstay of management 4 . Oligodendrocytes (OLs) and their precursors (oligodendrocyte precursor cells, OPCs) comprise the major cell types implicated in PWMI, which involves an arrest of differentiation of OPCs and a reduction in mature OLs and myelin formation [5][6][7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Minimum Effective Dose of Clemastine in a Mouse Model of Preterm White Matter Injury

Odell,

Jabassini,

Schniedewind

et al. 2024

Preprint

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BackgroundPreterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification if the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day.MethodsMouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine fumarate at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given orally to hypoxia-exposed pups. At P14, myelination was assessed by immunohistochemistry and electron microscopy to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment.ResultsClemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax44.0 ng/mL, t1/24.6 hours, and AUC24280.1 ng*hr/mL.ConclusionBased on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI.Key PointsPreterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates.Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment.The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials.We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

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Emerging neuroprotective interventions in periventricular leukomalacia - A systematic review of preclinical studies

Cited by 9 publications

References 187 publications

RETRACTED ARTICLE: PSB0788 ameliorates maternal inflammation‐induced periventricular leukomalacia-like injury

RETRACTED ARTICLE: PSB0788 ameliorates maternal inflammation‐induced periventricular leukomalacia-like injury

Melatonin Use during Pregnancy and Lactation Complicated by Oxidative Stress: Focus on Offspring’s Cardiovascular–Kidney–Metabolic Health in Animal Models

Minimum Effective Dose of Clemastine in a Mouse Model of Preterm White Matter Injury

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