Digirseophene A promotes recovery in injured developing cerebellum via AMPK/AKT/GSK3ß pathway-mediated neural stem cell proliferation.

Neural stem cells (NSCs) exhibit a remarkable capacity for self-renewal and have the potential to differentiate into various neural lineage cells, which makes them pivotal in the management of neurological disorders. Harnessing the inherent potential of endogenous NSCs for enhancing nerve repair and regeneration represents an optimal approach to addressing diseases of the nervous system. In this study, we explored the potential of a novel benzophenone derivative named Digirseophene A (DGA), which was isolated from the endophytic fungus Corydalis tomentella. Previous experiments have extensively identified and characterized DGA, revealing its unique properties. Our findings demonstrate the remarkable capability of DGA to stimulate neural stem cell proliferation, both in vitro and in vivo. Furthermore, we established a model of radiation-induced cerebellar injury to assess the effects of DGA on the distribution of different cell subpopulations within the damaged cerebellum, thereby suggesting its beneficial role in cerebellar repair. In addition, our observations on a primary NSCs model revealed that DGA significantly increased cellular oxygen consumption, indicating increased energy and metabolic demands. By utilizing various pathway inhibitors in combination with DGA, we successfully demonstrated its ability to counteract the suppressive impacts of AMPK and GSK3ß inhibitors on NSC proliferation. Collectively, our research results strongly suggest that DGA, as an innovative compound, exerts its role in activating NSCs and promoting injury repair through the regulation of the AMPK/AKT/GSK3ß pathway.

Cerebellar injury in preterm infants less than 28 weeks gestational age.

BACKGROUND: Cerebellar injury is one of the perinatal complications in preterm infants. Recent studies have highlighted the effect of perinatal complications on neurological morbidity. We investigated the perinatal risk factors and morbidity for cerebellar injury in extremely premature infants. METHODS: This retrospective cohort study included 285 infants born between April 2009 and December 2020 at gestational age <28 weeks at our institution. The infants were divided into two groups based on magnetic resonance imaging findings: those with and without cerebellar injury. We performed a statistical analysis of the perinatal background and short-term morbidity of the two groups. RESULTS: Significant differences (p < 0.05) were observed between the groups with respect to the perinatal background, especially gestational weeks, birthweight, and hemoglobin values at birth. In the short-term morbidity, significant differences (p < 0.05) were observed in the incidence of respiratory distress syndrome, chronic lung disease, hydrocephalus, severe intraventricular hemorrhage (IVH), and cerebellar hemorrhage. Extensive cerebellar lesions, such as cerebellar agenesis or global cerebellar hypoplasia, accounted for 11 of the 22 cases of cerebellar injury; seven of the 11 cases had severe IVH in addition to cerebellar hemorrhage. CONCLUSIONS: Gestational age was significantly lower in the cerebellar injury group. The combination of severe IVH and cerebellar hemorrhage may promote cerebellar injury.

Cerebellar injury induced by cadmium via disrupting the heat-shock response.

Cadmium (Cd) is a food contaminant that poses serious threats to animal health, including birds. It is also an air pollutant with well-known neurotoxic effects on humans. However, knowledge on the neurotoxic effects of chronic Cd exposure on chicken is limited. Thus, this study assessed the neurotoxic effects of chronic Cd on chicken cerebellum. Chicks were exposed to 0 (control), 35 (low), and 70 (high) mg/kg of Cd for 90 days, and the expression of genes related to the heat-shock response was investigated. The chickens showed clinical symptoms of ataxia, and histopathology revealed that Cd exposure decreased the number of Purkinje cells and induced degeneration of Purkinje cells with pyknosis, and some dendrites were missing. Moreover, Cd exposure increased the expression of heat-shock factors, HSF1, HSF2, and HSF3, and heat-shock proteins, HSP60, HSP70, HSP90, and HSP110. These changes indicate that HSPs improve the tolerance of the cerebellum to Cd. Conversely, the expressions of HSP10, HSP25, and HSP40 were decreased significantly, which indicated that Cd inhibits the expression of small heat-shock proteins. However, HSP27 and HSP47 were upregulated following low-dose Cd exposure, but downregulated under high-dose Cd exposure. This work sheds light on the toxic effects of Cd on the cerebellum, and it may provide evidence for health risks posed by Cd. Additionally, this work also identified a novel target of Cd exposure in that Cd induces cerebellar injury by disrupting the heat-shock response. Cd can be absorbed into chicken's cerebellum through the food chain, which eventually caused cerebellar injury. This study provided a new insight that chronic Cd-induced neurotoxicity in the cerebellum is associated with alterations in heat-shock response-related genes, which indicated that Cd through disturbing heat-shock response induced cerebellar injury.

Nano-selenium alleviates cadmium-induced cerebellar injury by activating metal regulatory transcription factor 1 mediated metal response.

This study aims to investigate the role of metal regulatory transcription factor 1 (MTF1)-mediated metal response in cadmium (Cd)-induced cerebellar injury, and to evaluate the antagonistic effects of nano-selenium (Nano-Se) against Cd toxicity. A total of 80 chicks (1 d old, male, Hy-Line Variety White) were randomly allocated to 4 treatment groups for 3 months: the control group (fed with a basic diet, n = 20), the Nano-Se group (basic diet with 1 mg/kg nano-Se 1 mg/kg Nano-Se in basic diet, n = 20), the Nano-Se + Cd group (basic diet with 1 mg/kg Nano-Se and 140 mg/kg CdCl2, n = 20) and the Cd group (basic diet with 140 mg/kg CdCl2 , n = 20). The results of the experiment showed that the Purkinje cells were significantly decreased with their degradation and indistinct nucleoli after Cd exposure. Moreover, exposure to Cd caused a significant accumulation of Cd and cupper. However, the contents of Se, iron, and zinc were decreased, thereby disturbing the metal homeostasis in the cerebellum. The Cd exposure also resulted in high levels of malondialdehyde (MDA) and down regulation of selenoprotein transcriptome. Furthermore, the expressions of MTF1, metallothionein 1 (MT1), MT2, zinc transporter 3 (ZNT3), ZNT5, ZNT10, zrt, irt-like protein 8 (ZIP8), ZIP10, transferrin (TF), ferroportin 1 (FPN1), ATPase copper transporting beta (ATP7B), and copper uptake protein 1 (CTR1) were inhibited by Cd exposure. However, all these changes were significantly alleviated by the supplementation of Nano-Se. This study proved that Cd could disorder metal homeostasis and induce oxidative stress, whereas Nano-Se could relieve all these negative effects caused by Cd via activating the MTF1-mediated metal response in the cerebellum of chicken.

Cadmium Through Disturbing MTF1-Mediated Metal Response Induced Cerebellar Injury.

Cadmium (Cd) is a toxic environmental contaminant, which bio-accumulate in animals through the food chain. Cerebellum is one of the primary target organs for Cd exposure. In this study, we established a chronic Cd exposure model; 60 chickens were treated with Cd (0 mg/kg, 35 mg/kg, 70 mg/kg) for 90 days. Clinical manifestations indicated that the chicken was depressed and has unstable gait under Cd exposure. Histopathological results indicated that Cd induced neuronal shrunken and indistinct nucleoli, and the number of Purkinje cells decreased significantly. Cerebellar metal contents were analyzed by ICP-MS. We found that Cd caused Cd and Cu accumulation and decreased the content of Se, Fe, and Zn, suggesting that Cd disturbed metal homeostasis. Besides, Cd treatment group also showed high levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) content and inhibited selenoprotein transcriptome, suggesting that Cd exposure resulted in oxidative stress. Notably, low-dose Cd exposure activated MTF1 mRNA and protein expression and its target metal-responsive genes, including MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B which indicate cellular adaptive response against Cd-induced damage. On the other hand, 70 mg/kg Cd downregulated MTF1-mediated metal response, which was involved in Cd-induced cerebellar injury in chicken. In conclusion, our data demonstrated that molecular mechanisms are associated with Cd-induced cerebellar injury due to disturbing MTF1-mediated metal response. This study indicated that the cerebellum is one of the target organs of Cd-induced toxicity. Additionally, Cd exposure induced metal dyshomeostasis in chicken's cerebellum, whereas this study found that lower level of Cd dose triggered the activation of the cytoprotective mechanism through activating the expression of MTF1 which regulate MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B expressions in cerebellum. However, MTF1-mediated metal response was inhibited under the exposure of high dose of Cd, which ultimately caused cerebellar injury. The present study provides a new insight that Cd through disturbed MTF1-mediated metal response disrupts metal homeostasis that induced cerebellar injury.

Comparative study of vestibular projection pathway connectivity in cerebellar injury patients and healthy adults.

OBJECTIVE: Cerebellar injury can not only cause gait and postural instability, nystagmus, and vertigo but also affect the vestibular system. However, changes in connectivity regarding the vestibular projection pathway after cerebellar injury have not yet been reported. Therefore, in the current study, we investigated differences in the connectivity of the vestibular projection pathway after cerebellar injury using diffusion tensor imaging (DTI) tractography. METHODS: We recruited four stroke patients with cerebellar injury. Neural connectivity in the vestibular nucleus (VN) of the pons and medulla oblongata in patients with cerebellar injury was measured using DTI. Connectivity was defined as the incidence of connection between the VN on the pons and medulla oblongata and target brain regions such as the cerebellum, thalamus, parieto-insular vestibular cortex (PIVC), and parietal lobe. RESULTS: At thresholds of 10 and 30, there was lower connectivity in the ipsilateral hemisphere between the VN at the medullar level and thalamus in the patients than in healthy adults. At a threshold of 1 and 10, the patient group showed lower VN connectivity with the PIVC than healthy adults. At a threshold of 1, VN connectivity with the parietal lobe in the contralateral hemisphere was lower in the patients than in healthy adults. Additionally, at a threshold of 30, VN connectivity at the pons level with the cerebellum was lower in healthy adults than in the patients. CONCLUSION: Cerebellar injury seems to be associated with decreased vestibular projection pathway connectivity, especially in the ipsilateral thalamus, PIVC, and contralateral parietal lobe.

Cerebellar mutism syndrome in pediatric head trauma with cerebellar injury.

PURPOSE: Cerebellar mutism syndrome (CMS) after cerebellar injury in pediatric head trauma is a poorly recognized condition that is not properly diagnosed or treated in our daily practice. We aimed to clinically identify this syndrome after isolated posttraumatic cerebellar injury and to propose pathophysiological explanation. METHODS: We retrospectively analyzed 8 consecutive children presenting with isolated cerebellar injury over 16 years. Clinical presentation, radiological type and localization of injury, clinical initial CMS symptoms, and long-term neurocognitive outcome were reviewed. RESULTS: Out of 8 patients presenting with isolated traumatic cerebellar injury, we diagnosed 2 cases with initial clinical symptoms of CMS. Both patients had an injury damaging median structures of the posterior fossa, especially the fourth ventricle and dentate nuclei. Initial symptoms lasted more than 1 month for one patient, who still presented concentration difficulties almost 1 year after the head injury. CONCLUSION: CMS after traumatic cerebellar injury does exist, even if it seems to be a very rare entity. It has to be better detected and studied in order to enrich pathophysiological knowledge about CMS of all etiologies and to bring our concerned patients the suitable follow-up and rehabilitative care that they could benefit from.

Cerebellar injury in premature neonates: Imaging findings and relationship with outcome.

Cerebellar hemorrhagic injury (CHI) is a common complication of preterm birth. There are now many studies that have investigated the developmental consequences of CHI. This review summarizes the present state of evidence regarding the outcomes of prematurity related CHI, with a particular focus on the neuroimaging characteristics associated with adverse outcomes. Studies published to date suggest that the severity of functional deficits is dependent on injury size and topography. However, the unique contribution of the CHI to outcomes still needs to be further investigated to ensure optimal prognostic counseling.

Comparison between retrosigmoid and translabyrinthine approaches for large vestibular schwannoma: focus on cerebellar injury and morbidities.

This study aimed to compare the surgical outcomes and morbidities of retrosigmoid and translabyrinthine approaches for large vestibular schwannoma (VS), with a focus on cerebellar injury and morbidities. Eighty-six consecutive patients with large VS, with a maximal extrameatal diameter > 3.0 cm, were reviewed between August 2010 and September 2018. The surgical outcomes, operating time, volume change of perioperative cerebellar edema, and inpatient rehabilitation related to cerebellar morbidities were compared between the two approaches. In total, 53 and 33 patients underwent the retrosigmoid and translabyrinthine approaches, respectively. The median follow-up time was 34.5 months. Surgical outcomes, including the extent of resection, tumor recurrence, and facial nerve preservation, showed no significant differences between the two groups. Patients who underwent the retrosigmoid approach showed a marginal trend for postoperative lower cranial nerve (LCN) dysfunction (P = 0.068). Although the approaching procedure time was longer in the translabyrinthine group, the tumor resection time was significantly longer in the retrosigmoid group (P = 0.001). The median change in the volume of the perioperative cerebellar edema was significantly larger in the retrosigmoid group (P < 0.001) and significantly related to the retrosigmoid approach, solid VS, and tumor resection time. Most cerebellar and LCN deficits were transient; however, the patients in the retrosigmoid group underwent inpatient rehabilitation more than those in the translabyrinthine group (P = 0.018). Both surgical approaches show equivalent surgical outcomes. Notably, the translabyrinthine approach for large VS has advantages in that it reduces cerebellar injury and related morbidities.

Cerebellar hypoplasia of prematurity: Causes and consequences.

As magnetic resonance imaging has been increasingly used to study brain injury and brain development in premature newborns, the prevalence of cerebellar abnormalities is increasingly recognized. The preterm cerebellum is highly vulnerable to a number of insults during its critical phase of growth and development throughout the period of prematurity and beyond. Direct cerebellar injury and additional factors such as supratentorial brain injury and glucocorticoid exposure adversely impact cerebellar growth and, consequently, increase the risk of neurodevelopmental disabilities. In this chapter the causes and consequences of cerebellar hypoplasia of prematurity are reviewed.

A composite neurobehavioral test to evaluate acute functional deficits after cerebellar haemorrhage in rats.

Cerebellar haemorrhage accounts for 5-10% of all intracerebral haemorrhages and leads to severe, long-lasting functional deficits. Currently, there is limited research on this stroke subtype, which may be due to the lack of a suitable composite neuroscoring system specific for cerebellar injury in rodents. The purpose of this study is to develop a comprehensive composite neuroscore test for cerebellar injury using a rat model of cerebellar haemorrhage. Sixty male Sprague-Dawley rats were subjected to either sham surgery or cerebellar haemorrhage. Twenty-four hours post-injury, neurological behaviour was evaluated using 17 cost-effective and easy-to-perform tests, and a composite neuroscore was developed. The composite neuroscore was then used to assess functional recovery over seven days after cerebellar haemorrhage. Differences in the composite neuroscore deficits for the mild and moderate cerebellar haemorrhage models were observed for up to five days post-ictus. Until now, a composite neuroscore for cerebellar injury was not available for rodent studies. Herein, using mild and moderate cerebellar haemorrhage rat models a composite neuroscore for cerebellar injury was developed and used to assess functional deficits after cerebellar haemorrhage. This composite neuroscore may also be useful for other cerebellar injury models.

Neuroimaging and neuropathological characteristics of cerebellar injury in extremely low birth weight infants.

OBJECTIVE: To determine the morphological characteristics and pathogenic factors of cerebellar injury in extremely low birth weight infants (ELBWI). SUBJECTS AND METHODS: Neuroimaging examination was performed on 17 eligible surviving ELBWI. Their MR images were assessed and classified its pattern of cerebellar injuries. Brain pathology was examined on 15 patients, who isolated this neuroimaging subjects. The trend of brain pathologies was revealed. RESULTS: Four types of morphological pattern were recognized: (i) the absence of major portions in the cerebellum (6/17 cases); (ii) focal cerebellar tissue loss (2/17); (iii) unilateral cerebellar atrophy/hypoplasia (3/17); (iv) small cerebellum with entrapped fourth ventricle (6/17). In cerebellar pathology, the most common findings were focal or widespread cerebellar subarachnoid hemorrhage (12/15) and olivocerebellar degeneration (12/15). In addition, one-third of the cases indicated remote cerebellar parenchymal hemorrhage. CONCLUSION: In MRI-defined lesions, the absence of major portions or focal tissue loss was associated with cerebellar parenchymal hemorrhage and/or hemorrhagic infarction, that is destructive lesion. On the other hand, small cerebellum or unilateral atrophy/hypoplasia, that is impaired development, may be related to the cerebellar neuron loss due to hemosiderin deposits in the surface of the cerebellum. The cerebellar injury in ELBWI is probably caused by not only environmental factors such as hemorrhage, hypoxia-ischemia, or other deleterious effect, but also immaturity of the rapidly growing cerebellum in particular gestational age.

Cerebellar Microstructural Organization is Altered by Complications of Premature Birth: A Case-Control Study.

OBJECTIVES: To compare regional cerebellar microstructure, as measured by diffusion tensor imaging (DTI), between preterm infants at term-equivalent age and healthy term-born control neonates, and to explore associations between DTI findings and clinical risk factors. STUDY DESIGN: In this case-control study, DTI studies were performed in 73 premature infants born ≤32 weeks and ≤1500 g birth weight and 73 full-term-born controls from healthy pregnancies. Using a region of interest approach, fractional anisotropy (FA) and mean diffusivity (MD) were extracted in 7 cerebellar regions including the anterior vermis, the right/left superior cerebellar peduncles, the middle cerebellar peduncle, and the dentate nuclei. To validate further our DTI measurements, we measured FA and MD in the genu of the corpus callosum and splenium. FA and MD were compared between groups using analyses of multiple linear regression models. RESULTS: Preterm infants at term-equivalent age presented with higher FA in the dentate nuclei (<.001) and middle cerebellar peduncle (.028), and lower MD in the vermis (.023) compared with controls. Conversely, preterm infants showed reduced FA and increased MD in both the genu of the corpus callosum and splenium (P < .001). Independent risk factors associated with altered FA and MD in the cerebellum included low Apgar score, supratentorial injury, compromised cardiorespiratory function, and surgery for necrotizing enterocolitis and patent ductus arteriosus. CONCLUSIONS: This DTI study provides evidence that complications of premature birth are associated with altered cerebellar microstructural organization when compared with term-born control infants.

The neurological outcomes of cerebellar injury in premature infants.

AIM: Cerebellar injury is a characteristic injury associated with preterm infants. However, the impact of cerebellar injury on the development of preterm infants is unclear. METHOD: We reviewed magnetic resonance image studies of preterm infants with cerebral palsy retrospectively and evaluated the developmental outcomes. RESULTS: Cerebellar injury was recognized in 9 (2.4%) of 381 patients with cerebral palsy who were born preterm. The median gestational age was 26 (range 23-32) weeks and the median birth weight was 938 (range 492-1450) g. Seven of the nine patients had severe symmetric injuries to the inferior cerebellar hemispheres, resulting in a pancake-like appearance of the residual upper cerebellum. Supratentorial lesions were also recognized: periventricular leukomalacia in seven; atrophy of the basal ganglia in two; and intraventricular hemorrhage in two. Importantly, the motor dysfunction was related to the reduction in the white matter volume and severity of basal ganglia atrophy, but not to the cerebellar injury. Four of the nine patients could walk without limitations despite extensive cerebellar disruption. Only four patients could speak meaningful words during the study and only one spoke two-word sentences. INTERPRETATION: The patients with cerebellar injury might have a communication handicap, rather than altered motor function. Prematurity-related cerebellar complications require more attention in terms of cognitive and speech function, in addition to neuromotor development.

Cerebellar injury in preterm children with cerebral palsy after intraventricular hemorrhage: Prevalence and relationship to functional outcomes.

OBJECTIVES: To elucidate the prevalence of cerebellar injury and its relationship to functional outcomes in preterm children with cerebral palsy (CP) after intraventricular hemorrhage (IVH). PARTICIPANTS: We selected 69 children (40 males and 29 females, aged between 6 and 13 years) out of 2049 with cerebral palsy who visited Morinomiya Hospital, the regional center hospital for CP in West Japan. The inclusion criteria were (1) gestational age under 36 weeks at birth, (2) clear history of postnatal intraventricular hemorrhage, and (3) age at investigation over 6 years old. Those without sufficient imaging study or functional evaluation were excluded. METHODS: The participants were divided into four groups according to the presence of post-hemorrhagic hydrocephalus (PH) and cerebellar injury (CI): PH+/CI+, PH+/CI-, PH-/CI+, and PH-/CI-. Type of CP, ability to walk, verbal function, the incidence of severe visual impairment, and the complication of epilepsy were investigated and compared among the groups. RESULTS: The gestational ages of the participants were between 22 and 34 weeks, and their birth weight was between 412 and 1788 g. PH and CI were found in 39 (57%) and 40 (58%) children, respectively. Both the PH+/CI+ group (n=31) and the PH-/CI+ group (n=9) showed significantly lower walking and verbal abilities and a higher incidence of epilepsy than the PH-/CI- group (n=21), while the PH+/CI- group showed no significant difference from the PH-/CI- group. Severe visual impairment was found only in the PH+/CI+ group and the PH-/CI+ group. CONCLUSIONS: The prevalence of CI in preterm children with CP after IVH (58%) was almost the same as that of PH. CI is one of the most significant complications in preterm infants, affecting motor and verbal functions and being associated with epilepsy more than PH.

Outcome of Cerebellar Injury with Intraventricular Hemorrhage.

Investigators from the Department of Pediatric Neurology, Morinomiya Hospital, Osaka, Japan performed a retrospective IRB approved study of the prevalence of cerebellar injury (CI) and effect on functional outcomes among preterm children with intraventricular hemorrhage (IVH) and cerebral palsy (CP), comparing them to infants with post-hemorrhagic hydrocephalus (PH).