neuronal degeneration
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In Alzheimer's disease (AD), amyloid β deposition-induced hippocampal synaptic dysfunction generally begins prior to neuronal degeneration and memory impairment. Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective in various animal models of neurodegeneration. In this study, we aimed to investigate the effects of LBE on the synapse loss in AD through the avenue of the retina in a triple transgenic mouse model of AD (3xTg-AD). We fed 3xTg-AD mice with low (200 mg/kg) or high (2 g/kg) dose hydrophilic LBE daily for 2 months from the starting age of 4- or 6-month-old. For those started at 6 month age, at 1 month (though not 2 months) after starting treatment, mice given high dose LBE showed a significant increase of a wave and b wave in scotopic ERG. After 2 months of treatment with high dose LBE, calpain-2, calpain-5, and the oxidative RNA marker 8-OHG were downregulated, and presynaptic densities in the inner plexiform layer but not the outer plexiform layer of the retina were significantly increased, suggesting the presynaptic structure of retina was preserved. Our results indicate that LBE feeding may preserve synapse stability in the retina of 3xTg-AD mice, probably by decreasing both oxidative stress and intracellular calcium influx. Thus, LBE might have potential as a neuroprotectant for AD through synapse preservation.

White matter disorders of the CNS such as MS, lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery. Most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined non-human primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculo-motor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This non-human primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair pro-myelinating/neuroprotective therapies to the clinic for myelin disorders such as MS.

Parkinson’s disease (PD) is a complicated and incapacitating neurodegenerative malady that emanates following the dopaminergic (DArgic) nerve cell deprivation in the substantia nigra pars compacta (SN-PC). The etiopathogenesis of PD is still abstruse. Howbeit, PD is hypothesized to be precipitated by an amalgamation of genetic mutations and exposure to environmental toxins. The aggregation of α-synucelin within the Lewy bodies (LBs), escalated oxidative stress (OS), autophagy-lysosome system impairment, ubiquitin-proteasome system (UPS) impairment, mitochondrial abnormality, programmed cell death, and neuroinflammation are regarded as imperative events that actively participate in PD pathogenesis. The central nervous system (CNS) relies heavily on redox-active metals, particularly iron (Fe) and copper (Cu), in order to modulate pivotal operations, for instance, myelin generation, synthesis of neurotransmitters, synaptic signaling, and conveyance of oxygen (O2). The duo, namely, Fe and Cu, following their inordinate exposure, are viable of permeating across the blood–brain barrier (BBB) and moving inside the brain, thereby culminating in the escalated OS (through a reactive oxygen species (ROS)-reliant pathway), α-synuclein aggregation within the LBs, and lipid peroxidation, which consequently results in the destruction of DArgic nerve cells and facilitates PD emanation. This review delineates the metabolism of Fe and Cu in the CNS, their role and disrupted balance in PD. An in-depth investigation was carried out by utilizing the existing publications obtained from prestigious medical databases employing particular keywords mentioned in the current paper. Moreover, we also focus on decoding the role of metal complexes and chelators in PD treatment. Conclusively, metal chelators hold the aptitude to elicit the scavenging of mobile/fluctuating metal ions, which in turn culminates in the suppression of ROS generation, and thereby prelude the evolution of PD.

Objectives. Recent resting-state functional magnetic resonance imaging (fMRI) studies have focused on glaucoma-related neuronal degeneration in structural and spontaneous functional brain activity. However, there are limited studies regarding the differences in the topological organization of the functional brain network in patients with glaucoma. In this study, we aimed to assess both potential alterations and the network efficiency in the functional brain networks of patients with primary angle-closure glaucoma (PACG). Methods. We applied resting-state fMRI data to construct the functional connectivity network of 33 patients with PACG ( 54.21 ± 7.21   years ) and 33 gender- and age-matched healthy controls ( 52.42 ± 7.80   years ). The differences in the global and regional topological brain network properties between the two groups were assessed using graph theoretical analysis. Partial correlations between the altered regional values and clinical parameters were computed for patients with PACG. Results. No significant differences in global topological measures were identified between the two groups. However, significant regional alterations were identified in the patients with PACG, including differences within visual and nonvisual (somatomotor and cognition-emotion) regions. The normalized clustering coefficient and normalized local efficiency of the right superior parietal gyrus were significantly correlated with the retinal fiber layer thickness (RNFLT) and the vertical cup to disk ratio (V C/D). In addition, the normalized node betweenness of the left middle frontal gyrus (orbital portion) was significantly correlated with the V C/D in the patients with PACG. Conclusions. Our results suggest that regional inefficiency with decrease and compensatory increase in local functional properties of visual and nonvisual nodes preserved the brain network of the PACG at the global level.

Background: The structural integrity of the hippocampus and the entorhinal cortex appears to be a prerequisite for normal acquisition of information about relational and contextual representation. Increased exposures to pyrethroids by pregnant women and children have raised concerns over their potentials as developmental neurotoxicants. Objectives: We studied the histological changes on the hippocampus and entorhinal cortex of adolescent Wistar rats prenatally exposed to mosquito coil smoke (MCS). Methods: 30 adult Wistar rats (20 females, 10 males) were used for the study. Mating was induced, and pregnancy was confirmed. Pregnant animals were grouped into four, 3 animals per group. Group I was exposed to fresh air. Groups II, III, and IV were exposed to mosquito coil smoke for 4, 6 and 8 hours daily respectively throughout gestation period. On Post-natal day (PND) 29, experimental animals were humanely sacrificed and regions of the hippocampus and entorhinal cortex were processed for histological studies using H & E stain. Results and Conclusion: Our results showed that prenatal exposure to mosquito coil smoke caused neuronal degeneration, distortion in cytoarchitecture of cellular layers and vacuolations in the hippocampus and entorhinal cortex of prenatally exposed groups.

Background: The state of cortical neurons and astrocytes are pointers to the health of the brain. These cells are morphologically distorted by alcohol exposure. Intrauterine alcohol exposure remains a challenge with perinatal consequences. The role of exposure time and postnatal timeline on the degree of cortical cell derangement remains a subject of controversy till date. This study therefore examines alcohol exposure and postnatal changes on brain weight, cortical neurons and astrocytes at different developmental periods. Methods: Twenty mature female Wistar rats were time-mated and grouped into 4 groups. Group 1 (control) received distilled water (2 mL/kg), Groups 2, 3 and 4 were administered 2.5 mL/kg of 20% ethanol orally on the 4th, 11th and 18th days of gestation respectively. Rats produced litters and pups' brains were harvested and processed for H&E and Golgi Cox stains at the 3rd and 6th postnatal week. Neuronal and astrocytic densities in the cerebral cortex were evaluated. Results and Conclusion: There was statistically significant increase (p<0.05) in the density of degenerating neurons at the third postnatal week and sixth postnatal weeks in the experimental groups when compared with the control. There was also statistically significant increase (p<0.05) in astrocytic density in groups 2 and 4 at the 3rd postnatal week. There was no statistically significant difference (p>0.05) in the astrocytic densities across groups at the sixth postnatal week. It was concluded that intrauterine alcohol exposure in any of the developmental periods resulted in postnatal neuronal degeneration which persisted till the 6th week. However, increased astrocytic densities is a feature of 1st and 3rd trimester alcohol exposure noted in the 3rd but absent in the 6th postnatal week.

Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on Day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as Day 8 in rats (≥5x1013 vg/kg) and Day 14 in monkeys (≥3.3x1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species.

Abstract Human aging is the main risk factor for Parkinson’s disease (PD). To better understand age-related PD pathogenesis, we modeled PD with directly reprogrammed dopaminergic neurons (iDA) which preserve donor aging signatures. By transcriptome analysis and immunohistochemistry on postmortem tissues, we identified a sulfurtransferase, TSTD1, to be upregulated in aged and diseased individuals. TSTD1 catalyzes sulfur transfer from thiosulfate to glutathione (GSH). GSH and cysteine were significantly decreased in dopaminergic (DA) neurons with TSTD1 overexpression. Lower intracellular H2S levels and mitochondrial membrane potential (MMP) were identified in aged, PD iDA, and TSTD1 overexpressing embryonic stem cell (ES)-derived DA neurons. TSTD1 overexpression could lead to GAPDH inhibition and energy deficiency in neurons. We hypothesize that TSTD1 upregulation in aged and PD individuals could disrupt sulfur metabolism which compromises anti-oxidant capacity and energy production in neurons; both of these mechanisms have been implicated as triggers for DA neuronal degeneration in PD.