A Promising Combination: PACAP and PARP Inhibitor Have Therapeutic Potential in Models of Diabetic and Hypertensive Retinopathies

Diabetes and hypertension are complex pathologies with increasing prevalence nowadays. Their interconnected pathways are frequently manifested in retinopathies. Severe retinal consequences and their tight connections as well as their possible treatments are particularly important to retinal research. In the present, work we induced diabetes with streptozotocin in spontaneously hypertensive rats and treated them either with PACAP or olaparib and alternatively with both agents. Morphological and immunohistochemical analyses were carried out to describe cell-specific changes during pathologies and after different treatments. Diabetes and hypertension caused massive structural and cellular changes especially when they were elicited together. Hypertension was crucial in the formation of ONL and OPL damage while diabetes caused significant differences in retinal thickness, OPL thickness and in the cell number of the GCL. In diabetes, double neuroprotective treatment ameliorated changes of calbindin-positive cells, rod bipolar cells and dopaminergic amacrine cells. Double treatment was curative in hypertensive diabetic rat retinas, especially in the case of rod bipolar and parvalbumin-positive cells compared to untreated or single-treated retinas. Our results highlighted the promising therapeutic benefits of olaparib and PACAP in these severe metabolic retinal disorders.

Detection of Preventable Fetal Distress During Labor From Scanned Cardiotocogram Tracings Using Deep Learning

Despite broad application during labor and delivery, there remains considerable debate about the value of electronic fetal monitoring (EFM). EFM includes the surveillance of fetal heart rate (FHR) patterns in conjunction with the mother's uterine contractions, providing a wealth of data about fetal behavior and the threat of diminished oxygenation and cerebral perfusion. Adverse outcomes universally associate a fetal injury with the failure to timely respond to FHR pattern information. Historically, the EFM data, stored digitally, are available only as rasterized pdf images for contemporary or historical discussion and examination. In reality, however, they are rarely reviewed systematically or purposefully. Using a unique archive of EFM collected over 50 years of practice in conjunction with adverse outcomes, we present a deep learning framework for training and detection of incipient or past fetal injury. We report 94% accuracy in identifying early, preventable fetal injury intrapartum. This framework is suited for automating an early warning and decision support system for maintaining fetal well-being during the stresses of labor. Ultimately, such a system could enable obstetrical care providers to timely respond during labor and prevent both urgent intervention and adverse outcomes. When adverse outcomes cannot be avoided, they can provide guidance to the early neuroprotective treatment of the newborn.

Anti-Inflammatory Effects of the Novel Barbiturate Derivative MHY2699 in an MPTP-Induced Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and is caused by the death of dopamine neurons and neuroinflammation in the striatum and substantia nigra. Furthermore, the inflammatory response in PD is closely related to glial cell activation. This study examined the neuroprotective effects of the barbiturate derivative, MHY2699 [5-(4-hydroxy 3,5-dimethoxybenzyl)-2 thioxodihydropyrimidine-4,6(1H,5H)-dione] in a mouse model of PD. MHY2699 ameliorated MPP⁺-induced astrocyte activation and ROS production in primary astrocytes and inhibited the MPP⁺-induced phosphorylation of MAPK and NF-κB. The anti-inflammatory effects of MHY2699 in protecting neurons were examined in an MPTP-induced mouse model of PD. MHY2699 inhibited MPTP-induced motor dysfunction and prevented dopaminergic neuronal death, suggesting that it attenuated neuroinflammation. Overall, MHY2699 has potential as a neuroprotective treatment for PD.

A Mouse Model of Nigrostriatal Dopaminergic Axonal Degeneration As a Tool for Testing Neuroprotectors

Degeneration of nigrostriatal dopaminergic neurons in Parkinsons disease begins from the axonal terminals in the striatum and, then, in retrograde fashion, progresses to the cell bodies in the substantia nigra. Investigation of the dynamics of axonal terminal degeneration may help in the identification of new targets for neuroprotective treatment and be used as a tool for testing potential drugs. We have shown that the degeneration rate of dopaminergic axonal terminals changes over time, and that the striatal dopamine concentration is the most sensitive parameter to the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This model was validated using neuroprotectors with well-known mechanisms of action: the dopamine transporter inhibitor nomifensine and SEMAX peptide that stimulates the secretion of endogenous neurotrophic factors or acts as an antioxidant. Nomifensine was shown to almost completely protect dopaminergic fibers from the toxic effect of MPTP and maintain the striatal dopamine concentration at the control level. However, SEMAX, slightly but reliably, increased striatal dopamine when administered before MPTP treatment, which indicates that it is more effective as an inductor of endogenous neurotrophic factor secretion rather than as an antioxidant.

Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy

The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.

Modulated Neuroprotection in Unresponsive Wakefulness Syndrome after Severe Traumatic Brain Injury

Background: We aimed to assess the effects of modulated neuroprotection with intermittent administration in patients with unresponsive wakefulness syndrome (UWS) after severe traumatic brain injury (TBI). Methods: Retrospective analysis of 60 patients divided into two groups, with and without neuroprotective treatment with Actovegin, Cerebrolysin, pyritinol, L-phosphothreonine, L-glutamine, hydroxocobalamin, alpha-lipoic acid, carotene, DL-α-tocopherol, ascorbic acid, thiamine, pyridoxine, cyanocobalamin, Q 10 coenzyme, and L-carnitine alongside standard treatment. Main outcome measures: Glasgow Coma Scale (GCS) after TBI, Extended Glasgow Coma Scale (GOS E), Disability Rankin Scale (DRS), Functional Independence Measurement (FIM), and Montreal Cognitive Assessment (MOCA), all assessed at 1, 3, 6, 12, and 24 months after TBI. Results: Patients receiving neuroprotective treatment recovered more rapidly from UWS than controls (p = 0.007) passing through a state of minimal consciousness and gradually progressing until the final evaluation (p = 0.000), towards a high cognitive level MOCA = 22 ± 6 points, upper moderate disability GOS-E = 6 ± 1, DRS = 6 ± 4, and an assisted gait, FIM =101 ± 25. The improvement in cognitive and physical functioning was strongly correlated with lower UWS duration (−0.8532) and higher GCS score (0.9803). Conclusion: Modulated long-term neuroprotection may be the therapeutic key for patients to overcome UWS after severe TBI.

Long-Term Suppression of c-Jun and nNOS Preserves Ultrastructural Features of Lower Motor Neurons and Forelimb Function after Brachial Plexus Roots Avulsion

Brachial plexus root avulsions cause debilitating upper limb paralysis. Short-term neuroprotective treatments have reported preservation of motor neurons and function in model animals while reports of long-term benefits of such treatments are scarce, especially the morphological sequelae. This morphological study investigated the long-term suppression of c-Jun- and neuronal nitric oxide synthase (nNOS) (neuroprotective treatments for one month) on the motor neuron survival, ultrastructural features of lower motor neurons, and forelimb function at six months after brachial plexus roots avulsion. Neuroprotective treatments reduced oxidative stress and preserved ventral horn motor neurons at the end of the 28-day treatment period relative to vehicle treated ones. Motor neuron sparing was associated with suppression of c-Jun, nNOS, and pro-apoptotic proteins Bim and caspases at this time point. Following 6 months of survival, neutral red staining revealed a significant loss of most of the motor neurons and ventral horn atrophy in the avulsed C6, 7, and 8 cervical segments among the vehicle-treated rats (n = 4). However, rats that received neuroprotective treatments c-Jun JNK inhibitor, SP600125 (n = 4) and a selective inhibitor of nNOS, 7-nitroindazole (n = 4), retained over half of their motor neurons in the ipsilateral avulsed side compared. Myelinated axons in the avulsed ventral horns of vehicle-treated rats were smaller but numerous compared to the intact contralateral ventral horns or neuroprotective-treated groups. In the neuroprotective treatment groups, there was the preservation of myelin thickness around large-caliber axons. Ultrastructural evaluation also confirmed the preservation of organelles including mitochondria and synapses in the two groups that received neuroprotective treatments compared with vehicle controls. Also, forelimb functional evaluation demonstrated that neuroprotective treatments improved functional abilities in the rats. In conclusion, neuroprotective treatments aimed at suppressing degenerative c-Jun and nNOS attenuated apoptosis, provided long-term preservation of motor neurons, their organelles, ventral horn size, and forelimb function.

Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2’s effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29′s failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2’s neuroprotection.

Association of Routinely Measured Proinflammatory Biomarkers With Abnormal MRI Findings in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

Background: The neuroprotective treatment effect of therapeutic hypothermia (TH) following perinatal asphyxia may be negatively influenced by neonatal sepsis and concomitant inflammation. We aimed to correlate routinely used blood biomarkers for perinatal sepsis in cooled asphyxiated newborns with MRI findings.Methods: Perinatal data was retrospectively collected from 67 cooled asphyxiated newborns. Levels of C-reactive protein (CRP), white blood cells and platelets were analyzed before, during and after TH. Interleukin-6 blood levels were analyzed before initiation of TH. Magnetic resonance imaging (MRI) on postnatal day 5–7 was used defining short-term outcome. Adverse outcome was defined as death or adverse MRI findings. Amplitude-integrated electroencephalography (aEEG) was additionally analyzed and correlated with short-term MRI outcome.Results: Forty-nine newborns had favorable short-term MRI outcome. Perinatal data referring to perinatal sepsis did not differ significantly between groups. IL-6 levels before initiation of TH and CRP levels on day three and after TH were significantly higher in newborns with adverse short-term MRI outcome. Males with adverse short-term MRI outcome had significantly increased CRP values at the end of the cooling phase. aEEG strongly correlated with short-term MRI outcome.Conclusion: Routinely used blood biomarkers may be helpful early identifying newborns at high risk of unfavorable outcome and in need of close neurodevelopmental follow-up.

Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence

Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.