Motor and somatosensory degenerative myelopathy responsive to pantothenic acid in piglets.

This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.

Histomorphological evaluations on the frontal cortex extrapyramidal cell layer following administration of N-Acetyl cysteine in aluminum induced neurodegeneration rat model.

Aluminum is a potent neurotoxin used in animal models of neurodegenerative diseases like Alzheimer's disease (AD), in which oxidative stress mediates tissue pathogenesis in vivo. N-acetyl cysteine (NAC) is a glutathione precursor with reported antioxidant and neuroprotective potentials. Recent therapy for combating AD is known to provide only symptomatic relief thus necessitating the discovery of new drugs and their mechanism of action. This study was aimed to demonstrate the in vivo neuroprotective effect of NAC against aluminum (Al3+)-induced neuro-degeneration in rats (a model for AD). Twenty- five (25) adult male Wistar rats used for this study were divided into 5 groups: Group A = Control, B = Aluminum chloride (200 mg/kg), C = 1000 mg/kg of NAC + Aluminum chloride (200 mg/kg), D = 1000 mg/kg of NAC, E = Aluminum chloride (200 mg/kg) was orally administered daily for 3 weeks and discontinued for one week. Frontal Cortex harvested for histological analysis using Haematoxylin and Eosin stain, Cresyl Fast Violet stain for Nissl granules and Glial fibrillary acidic protein immunohistochemistry specific for astrocytes. Aluminum significantly induced oxidative stress, coupled with marked neurons necrosis, chromatolysis and gliosis in the frontal cortex, upon NAC administration, there was neuro anti-inflammatory response as seen in the significant reduction in astrocytes expression, neuronal cell death and Nissl body aggregation which attenuates neuropathological deficits induced by Al3+. It was shown that aluminum is a neurotoxin mediating AD-like oxidative stress, NAC has a therapeutic potential associated with its potent in vivo interaction with astrocytes in response to Al3+ neuro-inflammation seen in positive expression of Nissl granules and glial cells in addition to possibility of endogenous glutathione neuroprotection after withdrawal of stress mediator in neurodegeneration. Graphical abstract.

Equine Dysautonomia.

Equine dysautonomia (ED; also known as equine grass sickness) is a neurological disease of unknown cause, which primarily affects grazing adult horses. The clinical signs reflect degeneration of specific neuronal populations, predominantly within the autonomic and enteric nervous systems, with disease severity and prognosis determined by the extent of neuronal loss. This review is primarily focused on the major clinical decision-making processes in relation to ED, namely, (1) clinical diagnosis, (2) selection of appropriate ancillary diagnostic tests, (3) obtaining diagnostic confirmation, (4) selection of treatment candidates, and (5) identifying appropriate criteria for euthanasia.

Bilateral stringhalt associated with Hypochaeris radicata in Uruguayan horses.

We reported thirteen cases of bilateral stringhalt associated with Hypochaeris radicata that occurred in horses in Uruguay during a severe drought in the summer of 2023. All horses were affected chronically and progressively by bilateral hyperflexion of hindlimbs. In two severely affected horses, the main histological lesions included neuronal chromatolysis and axonal spheroids in the ventral gray horn in the lumbar and sacral spinal cord and axonal degeneration and digestion chambers in ventral roots fibers and long peripheral nerves. We suggest that in addition to injuries to peripheral nerves, lesions in the spinal cord play an important role in the clinical signs of stringhalt in horses.

Development of a Deep Learning Model for the Analysis of Dorsal Root Ganglion Chromatolysis in Rat Spinal Stenosis.

Objective: To create a deep learning (DL) model that can accurately detect and classify three distinct types of rat dorsal root ganglion neurons: normal, segmental chromatolysis, and central chromatolysis. The DL model has the potential to improve the efficiency and precision of neuron classification in research related to spinal injuries and diseases. Methods: H&E slide images were divided into an internal training set (80%) and a test set (20%). The training dataset was labeled by two pathologists using pre-defined grades. Using this dataset, a two-component DL model was developed with the first component being a convolutional neural network (CNN) that was trained to detect the region of interest (ROI) and the second component being another CNN used for classification. Results: A total of 240 lumbar dorsal root ganglion (DRG) pathology slide images from rats were analyzed. The internal testing results showed an accuracy of 93.13%, and the external dataset testing demonstrated an accuracy of 93.44%. Conclusion: The DL model demonstrated a level of agreement comparable to that of pathologists in detecting and classifying normal and segmental chromatolysis neurons, although its agreement was slightly lower for central chromatolysis neurons. Significance: DL in improving the accuracy and efficiency of pathological analysis suggests that it may have a role in enhancing medical decision-making.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

Alpha lipoic acid reverses scopolamine-induced spatial memory loss and pyramidal cell neurodegeneration in the prefrontal cortex of Wistar rats.

Neurodegenerative disorders are linked to oxidative tissue damage characterized by gradual loss of cognitive functions and neuronal cells. Alpha-lipoic acid (AHA) has a strong antioxidant property. Scopolamine is an anti-muscarinic agent used to study the mechanism of memory loss in an animal model. This study is aimed at evaluating the antioxidant role of alpha lipoic acid in reversing scopolamine induced memory loss and neurodegenerative process in the prefrontal cortex of Wistar rats. Twenty adult male Wistar rats used were divided into four groups (n = 5): Group 1 received vehicle (Control), Group 2 had scopolamine (1 mg/kg, i.p) for 4 days, Group 3 received AHA (200 mg/kg, p.o) for 10 days while Group 4 were pretreated with scopolamine (1 mg/kg, i.p) for 4 days followed by oral administration of 200 mg/kg of AHA for 10 days. The rats were subjected to Y-maze test to assess their spatial memory. The rats were euthanized, the prefrontal area was excised and fixed in 10% formol-calcium and processed for Haematoxylin and Eosin, Cresyl fast violet for Nissl Bodies (Ribosome), and Glial Fibrillary Acidic Protein (GFAP) stains. Scopolamine caused a significant decline in spatial working memory, prefrontal neuron cell loss, and increased proliferation of reactive astrocytes (astrogliosis) when compared with the control and AHA treated group. AHA process of reversing scopolamine-induced memory deficit, prefrontal neuron cell loss, and generation of reactive astrocytes (astrogliosis) is mediated by its antioxidant mediated positive modulation of astrocyte-neuronal interaction during neuroinflammation in response to oxidative tissue damage.

Chromatolysis: Do injured axons regenerate poorly when ribonucleases attack rough endoplasmic reticulum, ribosomes and RNA?

After axonal injury, chromatolysis (fragmentation of Nissl substance) can occur in the soma. Electron microscopy shows that chromatolysis involves fission of the rough endoplasmic reticulum. In CNS neurons (which do not regenerate axons back to their original targets) or in motor neurons or dorsal root ganglion neurons denied axon regeneration (e.g., by transection and ligation), chromatolysis is often accompanied by degranulation (loss of ribosomes from rough endoplasmic reticulum), disaggregation of polyribosomes and degradation of monoribosomes into dust-like particles. Ribosomes and rough endoplasmic reticulum may also be degraded in autophagic vacuoles by ribophagy and reticulophagy, respectively. In other words, chromatolysis is disruption of parts of the protein synthesis infrastructure. Whereas some neurons may show transient or no chromatolysis, severely injured neurons can remain chromatolytic and never again synthesize normal levels of protein; some may atrophy or die. Ribonuclease(s) might cause the following features of chromatolysis: fragmentation and degranulation of rough endoplasmic reticulum, disaggregation of polyribosomes and degradation of monoribosomes. For example, ribonucleases in the EndoU/PP11 family can modify rough endoplasmic reticulum; many ribonucleases can degrade mRNA causing polyribosomes to unchain and disperse, and they can disassemble monoribosomes; Ribonuclease 5 can control rRNA synthesis and degrade tRNA; Ribonuclease T2 can degrade ribosomes, endoplasmic reticulum and RNA within autophagic vacuoles; and Ribonuclease IRE1α acts as a stress sensor within the endoplasmic reticulum. Regeneration might be improved after axonal injury by protecting the protein synthesis machinery from catabolism; targeting ribonucleases using inhibitors can enhance neurite outgrowth and could be a profitable strategy in vivo. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018.

Neuronal chromatolysis in the subgemmal plexus of gustatory papillae in horses with grass sickness.

REASONS FOR PERFORMING STUDY: Diagnosis of equine grass sickness (EGS) can be challenging. We hypothesised that subgemmal plexus neurons are chromatolytic in EGS. If correct, histopathological examination of gustatory papillae biopsies could aid premortem diagnosis of EGS, and EGS could represent a spontaneous model of subgemmal neuronal chromatolysis to facilitate study of the pathology of structures involved in taste. OBJECTIVE: To compare subgemmal plexi and gustatory papillae in EGS and control horses. STUDY DESIGN: Observational study. METHODS: Conventional histology and immunohistochemistry were used to compare subgemmal plexi and gustatory papillae in post mortem samples from 10 EGS and 13 control horses. RESULTS: Chromatolytic neurons were present in all 57 EGS sections which had identifiable neurons, and in only one of 57 control sections. Blinded examination of all haematoxylin-eosin stained sections from each horse for chromatolysis facilitated accurate differentiation of EGS and control horses, with a sensitivity of 100% (95% confidence interval 93.7-100) and specificity of 98.2% (90.6-100) for diagnosing EGS; however, the presence of chromatolytic neurons in one control section indicated that multiple sections per horse must be analysed to achieve diagnostic accuracy. Equine grass sickness was not associated with alterations in taste bud density or morphology, proportion of taste buds with neurofilament immunopositive intragemmal axons or proportion of taste buds containing cells undergoing apoptosis, suggesting taste buds had adequate neurotrophic support at the time of sampling. Horses with EGS had no detectable alteration in lingual gland morphology, but had increased proportions of apoptotic lingual serous gland cells. CONCLUSIONS: While identification of chromatolytic subgemmal neurons in post mortem samples correctly differentiated EGS and control horses, further study is required to evaluate this technique for premortem EGS diagnosis. Equine grass sickness represents a spontaneous model of subgemmal neuronal chromatolysis that facilitates study of the pathology of structures involved in taste.

Compensatory Motor Neuron Response to Chromatolysis in the Murine hSOD1(G93A) Model of Amyotrophic Lateral Sclerosis.

We investigated neuronal self-defense mechanisms in a murine model of amyotrophic lateral sclerosis (ALS), the transgenic hSOD1(G93A), during both the asymptomatic and symptomatic stages. This is an experimental model of endoplasmic reticulum (ER) stress with severe chromatolysis. As a compensatory response to translation inhibition, chromatolytic neurons tended to reorganize the protein synthesis machinery at the perinuclear region, preferentially at nuclear infolding domains enriched in nuclear pores. This organization could facilitate nucleo-cytoplasmic traffic of RNAs and proteins at translation sites. By electron microscopy analysis, we observed that the active euchromatin pattern and the reticulated nucleolar configuration of control motor neurons were preserved in ALS chromatolytic neurons. Moreover the 5'-fluorouridine (5'-FU) transcription assay, at the ultrastructural level, revealed high incorporation of the RNA precursor 5'-FU into nascent RNA. Immunogold particles of 5'-FU incorporation were distributed throughout the euchromatin and on the dense fibrillar component of the nucleolus in both control and ALS motor neurons. The high rate of rRNA transcription in ALS motor neurons could maintain ribosome biogenesis under conditions of severe dysfunction of proteostasis. Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis. In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases. Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative diseases.

The biochemical pathways of central nervous system neural degeneration in niacin deficiency.

Neural degeneration is a very complicated process. In spite of all the advancements in the molecular chemistry, there are many unknown aspects of the phenomena of neurodegeneration which need to be put together. It is a common sequela of the conditions of niacin deficiency. Neural degeneration in Pellagra manifests as chromatolysis mainly in pyramidal followed by other neurons and glial cells. However, there is a gross lack of understanding of biochemical mechanisms of neurodegeneration in niacin deficiency states. Because of the necessity of niacin or its amide derivative NAD in a number of biochemical pathways, it is understandable that several of these pathways may be involved in the common outcome of neural degeneration. Here, we highlight five pathways that could be involved in the neuraldegeneration for which evidence has accumulated through several studies. These pathways are: 1) the tryptophan-kyneurenic acid pathway, 2) the mitochondrial ATP generation related pathways, 3) the poly (ADP-ibose) polymerase (PARP) pathway, 4) the BDNF-TRKB Axis abnormalities, 5) the genetic influences of niacin deficiency.

Intoxicação experimental por Aspergillus clavatus em ovinos / Experimental poisoning by Aspergillus clavatus in sheep

Descreve-se a reprodução experimental de doença neurológica em ovinos através da administração de bagaço de malte (resíduo cervejaria) contaminado com Aspergillus clavatus. Esse resíduo de cervejaria, cujas amostras revelaram cultura pura de A. clavatus, estava sendo utilizado em duas propriedades, onde ocorreram surtos da doença em bovinos. Os sinais clínicos iniciaram-se cerca de 2 a 6 dias após a administração do subproduto ou da cultura e a evolução clínica foi de 1,5 a 12 dias. Os sinais clínicos, que foram predominantemente locomotores e respiratórios, incluíram tremores musculares, hiperestesia, taquipnéia progressiva, rigidez de membros pélvicos (mais evidente à locomoção), fraqueza dos posteriores e decúbito. Um ovino também apresentou apoio ocasional sobre os boletos dos membros pélvicos. As anormalidades locomotoras e tremores eram intensificados pelo exercício. Entretanto, em 6 dos 7 ovinos, o apetite e a dipsia eram mantidas até próximo à morte ou eutanásia. O principal achado histológico consistia de degeneração e necrose neuronal cromatolítica em núcleos nervosos específicos do tronco encefálico, cornos ventrais da medula espinhal e gânglios espinhais, trigeminal, estrelado e celíaco. Três ovinos também apresentaram degeneração e necrose leves em músculos dos membros pélvicos e torácicos.

This paper describes the experimental reproduction of a neurological condition in sheep by the administration of a beer by-product contaminated with Aspergillus clavatus. Samples of this by-product, in which pure cultures of A. clavatus grew, originated from two farms where outbreaks of A. clavatus poisoning in cattle had occurred. The onset of symptomatology was 2 to 6 days after dosage with the contaminated beer by-product or pure A. clavatus culture. The clinical course lasted from one and a half to 12 days. Clinical signs were predominantly of locomotor and respiratory nature and included muscle tremors, hyperesthesia, and progressive tachypnea, rigidity of the pelvic limbs, posterior weakness, and recumbency. One sheep also showed occasional knuckling of fetlocks of the hind limbs. Gait abnormalities and tremors were more pronounced after exercise. In 6 of 7 sheep, appetite and dypsia were maintained until close to death or euthanasia. The main histological findings consisted of chromatolytic neuronal degeneration and necrosis in selected nuclei of the brain stem, the ventral horn of the spinal cord and the spinal, trigeminal, stellate and celiac ganglions. Three sheep also presented slight degenerative and necrotic changes in muscles of the pelvic and thoracic limbs.

Neurotoxicose em bovinos associada ao consumo de bagaço de malte contaminado por Aspergillus clavatus / Neurotoxicosis in cattle associated with consumption of beer residues contaminated with Aspergillus clavatus

Descrevem-se dois surtos de uma doença neurológica que afetou rebanhos bovinos leiteiros que consumiam bagaço de malte contaminado por Aspergillus clavatus no município de Viamão, estado do Rio Grande do Sul. A morbidade em ambos os surtos foi em torno de 30 por cento e a letalidade, 50 por cento e 100 por cento. A evolução clínica da doença variou de 5 a 64 dias. Dentre os animais que se recuperaram apenas um permaneceu com seqüelas locomotoras leves. Os sinais clínicos eram predominantemente locomotores e incluíam tremores musculares de intensidade variável, hiperestesia e membros pélvicos com ataxia, paresia e paralisia progessivas, e apoio sobre os boletos. Os distúrbios locomotores eram intensificados pelo exercício que, em geral, desencadeava quedas. Havia também marcada queda na produção leiteira, no entanto o apetite e a dipsia eram mantidos até próximo da morte ou eutanásia. Cinco bovinos foram necropsiados e destes dois apresentaram lesões macroscópicas nos músculos esqueléticos, principalmente nos membros pélvicos e torácicos caracterizadas por alterações necróticas e mineralização. No sistema nervoso, os principais achados consistiam de degeneração e necrose neuronal cromatolítica em núcleos nervosos específicos no tronco encefálico, nos cornos ventrais da medula espinhal e nos gânglios trigeminal, estrelado, celíaco e espinhais. Em dois bovinos havia adicionalmente degeneração walleriana nos funículos dorsais da medula espinhal e nervos isquiádico e fibular. O diagnóstico foi baseado nos dados epidemiológicos, sinais clínicos, achados de necropsia, histopatológicos e micológicos. Os aspectos epidemiológicos, clínicos e patológicos da enfermidade, além de possíveis mecanismos patogenéticos e diagnósticos diferenciais são discutidos.

Two outbreaks of a neurological disease affecting herds of dairy cattle that were fed moldy beer residues contaminated with Aspergillus clavatus in the county of Viamão, Rio Grande do Sul, Brazil, are described. The morbidity of both outbreaks was 30 percent and the lethality 50 percent and 100 percent. The clinical course varied from 5 to 64 days. Only one of the animals that recovered from the disease remained with slight locomotor sequels. Clinical signs were predominantly locomotor and included muscle tremors of varied intensity, hyperesthesia and progressive posterior ataxia, paresis and paralysis with knuckling of fetlocks of the hind limbs. Gait abnormalities were more pronounced after exercises which in general led to falling down. There was also reduced milk production, but appetite and water intake were maintained until close to death or euthanasia. From five cattle necropsied, two showed macroscopic lesions characterized by necrotic changes and mineralization in pelvic muscles and thoracic limbs. The main histological findings consisted of chromatolytic neuronal degeneration and necrosis in selected nuclei of the brain stem, the ventral horn of the spinal cord, and of the trigeminal, stellate celiac and spinal ganglions. In two cattle there was wallerian degeneration in dorsal funiculi of the spinal cord and ischiadic and fibular nerves. The diagnosis was based on epidemiological data, clinical signs, necropsy findings, histological lesions and mycological examination. Epidemiologic, clinical and pathologic aspects, pathogenetic mechanisms and differential diagnoses are discussed.

Brain-derived neurotrophic factor: a possible intermediate of progesterone action in the injured spinal cord

Progesterone (PROG), a steroid classically associated with reproductive functions, also provides neuroprotection to the lesioned peripheral and central nervous system, including the spinal cord. The latter is a target of PROG, as neurons and/or glial cells express intracellular receptors as well as membrane receptors for PROG. When spinal cord injury (SCI) is produced at the thoracic level, several genes become sensitive to PROG in the region caudal to the lesion site. Although the molecular mechanisms implicated in PROG neuroprotection remain elusive, several reports point to neurotrophic factors, their receptors and signaling cascades as possible intermediates of steroid action. Indeed, a 3-day course of PROG treatment to the injured animals increased the mRNA of brain-derived neurotrophic factor (BDNF) and BDNF immunoreactivity in perikaryon and processes of motoneurons, while neuronal chromatolytic changes were strongly prevented. Interestingly, previous data demonstrated that BDNF mimics some of these PROG effects in the spinal cord, suggesting that BDNF and PROG may share common intracellular pathways. Furthermore, PROG enhancement of endogenous BDNF may provide a local trophic support and regulate in a paracrine or autocrine fashion the function of neurons and glial cells to prevent cellular death after injury.