Small­molecule PKR­like endoplasmic reticulum kinase inhibitors as a novel targeted therapy for Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in worldwide and remains a therapeutic challenge due to the low efficacy of current treatments. Numerous studies have demonstrated the pivotal role of endoplasmic reticulum (ER) stress in PD pathogenesis. ER stress, followed by activation of the protein kinase RNA­like endoplasmic reticulum kinase (PERK)­dependent branch of the unfolded protein response signaling pathway, ultimately leads to neural cell death and dopaminergic neurodegeneration in PD. Therefore, the present study evaluated the effectiveness of the small­molecule PERK inhibitor LDN­87357 in an in vitro PD model using the human neuroblastoma SH­SY5Y cell line. To assess the mRNA expression levels of the pro­apoptotic ER stress markers, the TaqMan Gene Expression Assay was performed. Cytotoxicity was assessed using a colorimetric 2,3­bis­(2­methoxy­4­nitro­5­sulfophenyl)­ 2H­tetrazolium­5­carboxanilide assay and apoptosis was assessed using a caspase­3 assay. Moreover, cell cycle progression was evaluated using flow cytometry. The results indicated that LDN­87357 treatment induced a significant decrease in ER stress markers gene expression in SH­SY5Y cells exposed to ER stress. Furthermore, LDN­87357 significantly increased viability, diminished apoptosis and restored the normal cell cycle distribution of SH­SY5Y cells after ER stress induction. Therefore, the evaluation of small­molecule PERK inhibitors, such as LDN­87357, may lead to the development of novel therapeutic strategies against PD.

Intramedullary Spinal Cord Abscess with Concomitant Spinal Degenerative Diseases: A Case Report and Systematic Literature Review.

Intramedullary spinal cord abscess (ISCA) is a rare clinical pathology of the central nervous system that usually accompanies other underlying comorbidities. Traditionally it has been associated with significant mortality and neurological morbidities because it is often difficult to diagnose promptly, owing to its nonspecific clinical and neuroimaging features. The mortality rate and the outcome of these infections have been improved by the introduction into clinical practice of antibiotics, advanced neuroimaging modalities, and immediate surgery. We report the case of a 65-year-old male patient who presented with a progressive spastic gait and lumbar pain, predominantly in the left leg. An MRI image revealed an expansile intramedullary cystic mass in the thoracic spinal cord, which was initially diagnosed as a spinal tumor. He underwent laminectomy and myelotomy, and eventually the pus was drained from the abscess. The follow-up MRI showed improvement, but the patient's paraplegia persisted. In light of his persistent hypoesthesia and paraplegic gait with developing neuropathic pain, he was readmitted, and an MRI of his lumbar spine revealed multilevel degenerative disease and tethered spinal cord syndrome with compression of the medulla at the L2-L3 level. The patient underwent central flavectomy with bilateral foraminotomy at the L2-L3 level, and the medulla was decompressed. Postoperatively, his neurological symptoms were significantly improved, and he was discharged from hospital on the third day after admission. In support of our case, we systematically reviewed the recent literature and analyzed cases published between 1949 and May 2022, including clinical features, mechanisms of infection, predisposing factors, radiological investigations, microbial etiologies, therapies and their duration, follow-ups, and outcomes. Initial clinical presentation can be misleading, and the diagnosis can be challenging, because this condition is rare and coexists with other spinal diseases. Hence, a high index of suspicion for making an accurate diagnosis and timely intervention is required to preclude mortality and unfavorable outcomes. Our case is a clear example thereof. Long-term follow-up is also essential to monitor for abscess recurrences.

Targeting NLRP3-Mediated Neuroinflammation in Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is the most common cause of dementia in the general population and, to date, constitutes a major therapeutic challenge. In the pathogenesis of AD, aggregates of amyloid ß (Aß) and neurofibrillary tangles (NFTs) containing Tau-microtubule-associated protein (tau) are known to trigger a neuroinflammatory response with subsequent formation of an inflammasome. In particular, the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is thought to play a crucial role in AD-related pathology. While the mechanisms for NLRP3 activation are not fully understood, it has been demonstrated that, after detection of protein aggregates, NLRP3 induces pro-inflammatory cytokines, such as interleukin 18 (IL-18) or interleukin 1ß (IL-1ß), that further potentiate AD progression. Specific inhibitors of NLRP3 that exhibit various mechanisms to attenuate the activity of NLRP3 have been tested in in vivo studies and have yielded promising results, as shown by the reduced level of tau and Aß aggregates and diminished cognitive impairment. Herein, we would like to summarize the current state of knowledge on NLRP3 inflammasome priming, activation, and its actual role in AD pathogenesis, and to characterize the NLRP3 inhibitors that have been studied most and their impact on AD-related pathology.

What Is Currently Known about Intramedullary Spinal Cord Abscess among Children? A Concise Review.

Intramedullary spinal cord abscesses (ISCA) are rare. Typical symptoms include signs of infection and neurological deficits. Symptoms among (younger) children can be highly uncharacteristic. Therefore, prompt and proper diagnoses may be difficult. Typical therapeutic options include antibiotics and neurosurgical exploration and drainage. In this review, we analyze published cases of ISCA among children. Most pediatric cases were found to be under the age of 6 years. The typical symptoms included motor deficits in 89.06%, infection signs in 85.94%, and sensory deficits in 39.06%. Urinary dysfunction was observed in 43.75%, and bowel dysfunction in 17.19%. The predisposing factors included dermal sinuses, (epi)dermoid cysts, prior infection, iatrogenic disorder, and trauma. The most common pathogens were: Staphylococcus aureus, Mycobacterium tuberculosis, Escherichia coli, and Proteus mirabilis. The pediatric population has good outcomes as 45.93% of patients had complete neurological recovery and only 26.56% had residual neurological deficits. Fifteen (23.44%) had persistent neurological deficits. Only one (1.56%) patient died with an ISCA. In two (3.13%) cases, there were no details about follow-up examinations.