Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aß). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aß. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aß and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aß. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aß clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.

The Possible Role of Brain-derived Neurotrophic Factor in Epilepsy.

Epilepsy is a neurological disease characterized by repeated seizures. Despite of that the brain-derived neurotrophic factor (BDNF) is implicated in the pathogenesis of epileptogenesis and epilepsy, BDNF may have a neuroprotective effect against epilepsy. Thus, the goal of the present review was to highlight the protective and detrimental roles of BDNF in epilepsy. In this review, we also try to find the relation of BDNF with other signaling pathways and cellular processes including autophagy, mTOR pathway, progranulin (PGN), and α-Synuclein (α-Syn) which negatively and positively regulate BDNF/tyrosine kinase receptor B (TrkB) signaling pathway. Therefore, the assessment of BDNF levels in epilepsy should be related to other neuronal signaling pathways and types of epilepsy in both preclinical and clinical studies. In conclusion, there is a strong controversy concerning the potential role of BDNF in epilepsy. Therefore, preclinical, molecular, and clinical studies are warranted in this regard.

Impact of Nutritional Interventions on Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The most prevalent type of dementia, especially in older persons, is Alzheimer's disease (AD), which has clinical signs of progressive cognitive decline and functional impairment. However, new research indicates that AD patients' dietary patterns and nutritional intake could hold the key to staving off some of the complications. Therefore, the primary aim of this investigation was to analyze various dietary patterns and the subsequent impact of the resulting nutritional intake on AD patients. Various online databases (PubMed, Scopus, Web of Science, and Google Scholar) were searched using appropriate keywords, reference searches, and citation searches. The databases were accessed using the search phrases "Alzheimer's disease," "dietary habits," "minerals," "nutritional profile," and "vitamins." Fifteen of the 21 investigations that we selected for our systematic review and subsequent meta-analysis revealed that micronutrient supplementation and some dietary patterns were helpful in alleviating a few of the symptoms of AD, especially with regard to the progression of dementia in the assessed patients. It was shown that dietary interventions and nutritional adjustments can considerably delay the onset of AD and the varying degrees of dementia that often accompany it. However, there were some areas of ambiguity in our findings because a few of the chosen studies did not document any noticeable improvements in the patient's conditions.

Role of brain renin-angiotensin system in depression: A new perspective.

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin-angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS-induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain-derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non-classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer's disease: a new perspective.

Alzheimer's disease (AD) is the most common type of dementia associated with amyloid beta (Aß) deposition. Dysfunction of the neuronal clearance pathway promotes the accumulation of Aß. The plasminogen-activating system (PAS) is controlled by various enzymes like tissue plasminogen activators (tPA). Neuronal tPA enhances the conversion of plasminogen to plasmin, which cleaves Aß; this function is controlled by many inhibitors of PAS, including a plasminogen-activating inhibitor (PAI-1) and neuroserpin. Therefore, the objective of the present narrative review was to explore the potential role of tPA/neuroserpin in the pathogenesis of AD. PAI-1 activity is increased in AD, which is involved in accumulating Aß. Progressive increase of Aß level during AD neuropathology is correlated with the over-production of PAI-1 with subsequent reduction of plasmin and tPA activities. Reducing plasmin and tPA activities promote Aß by reducing Aß clearance. Neuroserpin plays a critical role in the pathogenesis of AD as it regulates the expression and accumulation of Aß. Higher expression of neuroserpin inhibits the neuroprotective tPA and the generation of plasmin with subsequent reduction in the clearance of Aß. These observations raise conflicting evidence on whether neuroserpin is neuroprotective or involved in AD progression. Thus, neuroserpin over-expression with subsequent reduction of tPA may propagate AD neuropathology.

The Molecular Pathway of p75 Neurotrophin Receptor (p75NTR) in Parkinson's Disease: The Way of New Inroads.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease of the brain. PD is characterized by motor and non-motor symptoms. The p75 neurotrophin receptor (p75NTR) is a functional receptor for different growth factors including pro-brain derived neurotrophic factor (pro-BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Consequently, this review aimed to illustrate the detrimental and beneficial role of p75NTR in PD. Diverse studies showed that p75NTR and its downstream signaling are intricate in the pathogenesis of PD. Nevertheless, pro-apoptotic and pro-survival pathways mediated by p75NTR in PD were not fully clarified. Of note, p75NTR plays a critical role in the regulation of dopaminergic neuronal survival and apoptosis in the CNS. Particularly, p75NTR can induce selective apoptosis of dopaminergic neurons and progression of PD. In addition, p75NTR signaling inhibits the expression of transcription factors which are essential for the survival of dopaminergic neurons. Also, p75NTR expression is connected with the severity of dopaminergic neuronal injury. These verdicts implicate p75NTR signaling in the pathogenesis of PD, though the underlying mechanistic pathways remain not elucidated. Collectively, the p75NTR signaling pathway induces a double-sword effect either detrimental or beneficial depending on the ligands and status of PD neuropathology. Therefore, p75NTR signaling seems to be protective via phosphoinositide 3-kinase (PI3K)/AKT and Bcl-2 and harmful via activation of JNK, caspase 3, nuclear factor kappa B (NF-κB), and RhoA pathways.

Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator.

Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy's involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy.

Irisin/PGC-1α/FNDC5 pathway in Parkinson's disease: truth under the throes.

Parkinson's disease (PD) is considered one of the most common neurodegenerative brain diseases which involves the deposition of α-synuclein. Irisin hormone, a newly discovered adipokine, has a valuable role in diverse neurodegenerative diseases. Therefore, this review aims to elucidate the possible role of the irisin hormone in PD neuropathology. Irisin hormone has a neuroprotective effect against the development and progression of various neurodegenerative disorders by increasing the expression of brain-derived neurotrophic factor (BDNF). Irisin hormone has anti-inflammatory, anti-apoptotic, and anti-oxidative impacts, thereby reducing the expression of the pro-inflammatory cytokines and the progression of neuroinflammation. Irisin-induced PGC-1α could potentially prevent α-synuclein-induced dopaminergic injury, neuroinflammation, and neurotoxicity in PD. Inhibition of NF-κB by irisin improves PGC-1α and FNDC5 signaling pathway with subsequent attenuation of PD neuropathology. Therefore, the irisin/PGC-1α/FNDC5 pathway could prevent dopaminergic neuronal injury. In conclusion, the irisin hormone has a neuroprotective effect through its anti-inflammatory and antioxidant impacts with the amelioration of brain BDNF levels. Further preclinical and clinical studies are recommended in this regard.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

Constituents of Stachys plants as potential dual inhibitors of AChE and NMDAR for the treatment of Alzheimer's disease: a molecular docking and dynamic simulation study.

Alzheimer's disease (AD) is a chronic neurodegenerative condition characterized by progressive cognitive impairment. While the formation of ß-amyloid plaques and neurofibrillary tangles are the hallmarks features of AD, the downstream consequence of these byproducts is the disruption of the cholinergic and glutamatergic neural systems. Growing evidence for the existence of interplay between AChE and NMDARs has opened up new venues for the discovery of novel ligands endowed with anticholinesterase and NMDAR-blocking activity. Plants belonging to the stachys genus have been extensively explored for having a broad range of therapeutic applications and have been used traditionally for millennia, to treat various CNS-related disorders, which makes them the ideal source of novel therapeutics. The present study was designed to identify natural dual-target inhibitors for AChE and NMDAR deriving from stachys genus for their potential use in AD. Using molecular docking, drug-likeness-profiling, MD simulation and MMGBSA calculations, an in-house database of biomolecules pertaining to the stachys genus was shortlisted based on their binding affinity, overall stability and critical ADMET parameters. Pre- and post-MD analysis revealed that Isoorientin effectively binds to AChE and NMDAR with various vital interactions, exhibits a stable behavior with minor fluctuations relative to two clinical drugs used as positive control, and displays strong and consistent interactions that lasted for the majority of the simulation. Findings from this study have elucidated the rationale behind the traditional use of Stachys plants for the treatment of AD and could provide new impetus for the development of novel dual-target therapeutics for AD treatment.Communicated by Ramaswamy H. Sarma.

Neurological Implications of Vitamin B12 Deficiency in Diet: A Systematic Review and Meta-Analysis.

BACKGROUND: Vitamin B12 is one of the most important B-Vitamins that the human body needs on a daily basis, the lack of which can precipitate several neurological issues. OBJECTIVES: This systematic aimed to investigate the neurological implications of Vitamin B12 deficiency and the effects when B12 levels were corrected in susceptible individuals. METHODS: The databases PubMed-MEDLINE, Web of Science, Cochrane, and Scopus were all searched using pertinent keywords, reference searches, and citation searches. The terms used to access the database were "Cognition", "Dietary patterns", "Neurology", "Nutritional profile", and "Vitamin B12". RESULTS: Vitamin B12 was shown to noticeably improve cognition and other neurological parameters in the short term in older adults and the short-to-medium term in children; however, there was no perceived increase/improvement when the Vitamin was administered in the longer term, either alone or in conjunction with other similar nutritional interventions. CONCLUSION: Vitamin B12's role in the improvement of neurological functions over a long-term period remains somewhat inconclusive to date, as the majority of our selected control trials did not display much correlation between the two factors. However, Vitamin B12 did improve cognition levels in both children and older adults over a short course of administration.

Prevalence and prediction of pressure ulcers in admitted stroke patients in a tertiary care hospital.

Pressure ulcer (PU) is a localized injury to the skin or underlying tissues usually over a bony prominence, which results due to pressure or pressure in combination with shear. It is an expensive health care problem that have deterring impact on the length of hospitalization and cause extra nursing care time. Moreover, PUs negatively impacts patients' health related quality of life. High PUs prevalence figures were found in specialized hospital units such as intensive care unit (ICU), orthopedics, surgery, and also in stroke patients in medical units. The major purpose of this study is to assess the frequency of pressure ulcers in stroke patients at Ayub teaching hospital. The methodology used for carrying out the research was cross-sectional study conducted during months of September, October, and November 2020. Questionnaire was used to collect the data and well-informed written consent was taken from the patients. A total of 120 stroke patients were initially included with the intention to study the frequency of PUs among them. Different age groups were taken but majority (48.3%) belonged to the age group 31-60 years. Maximum patients were hypertensive (65%), while few of them were diabetic (35%). From the results of proposed work, it is found that out of 120 stroke patients, 75.8% presented with ischemic stroke while 24.2% presented with hemorrhagic stroke. 8.3% that is 10 out of 120 stroke patients developed pressure ulcers of grade 1 (1.7%), grade 2 (1.7%), grade 3 (2.5%), and grade 4 (2.5%) mostly in the sacral region (6.7%) and also on ankle (0.8%), and shoulder (0.8%) respectively. Patients in the study group had unsatisfactory hygiene (6.7%) were malnourished (11.7%) and were not using preventive mattresses (79.2%). Those at the risk of developing pressure ulcers were not being repositioned (6.7%) and did not had awareness (10%). Prevention and treatment used in ward is 100%. Conclusively, the frequency of pressure ulcers in stroke patients was determined to be 8.3% and the most frequent localization was sacrum. The PU care in this hospital is appropriate but still could be improved further by improving risk assessment, prevention specially use of air mattress and patient education regarding PUs. The main objective of the study is to identify the frequency of PUs in stroke patients and to highlight various factors that would avoid PUs development.

Brain Tumor/Mass Classification Framework Using Magnetic-Resonance-Imaging-Based Isolated and Developed Transfer Deep-Learning Model.

With the advancement in technology, machine learning can be applied to diagnose the mass/tumor in the brain using magnetic resonance imaging (MRI). This work proposes a novel developed transfer deep-learning model for the early diagnosis of brain tumors into their subclasses, such as pituitary, meningioma, and glioma. First, various layers of isolated convolutional-neural-network (CNN) models are built from scratch to check their performances for brain MRI images. Then, the 22-layer, binary-classification (tumor or no tumor) isolated-CNN model is re-utilized to re-adjust the neurons' weights for classifying brain MRI images into tumor subclasses using the transfer-learning concept. As a result, the developed transfer-learned model has a high accuracy of 95.75% for the MRI images of the same MRI machine. Furthermore, the developed transfer-learned model has also been tested using the brain MRI images of another machine to validate its adaptability, general capability, and reliability for real-time application in the future. The results showed that the proposed model has a high accuracy of 96.89% for an unseen brain MRI dataset. Thus, the proposed deep-learning framework can help doctors and radiologists diagnose brain tumors early.

Mycoplasma pneumoniae and Schistosoma mansoni co-infection in a young patient with extensive longitudinal acute transverse myelitis.

INTRODUCTION: Acute transverse myelitis is an uncommon inflammatory, intramedullary, disorder of the spinal cord. Spastic paraplegia, impaired sphincter functions, and sensory loss, with sensory level, are the clinical manifestations of this devastating disorder. The utilization of magnetic resonant imaging (MRI) contributes to the surge in the diagnosis of more ATM cases. Although the causes of ATM are numerous, both Mycoplasma pneumoniae and Schistosoma mansoni are uncommon causes and their co-existence in the same patient has not been reported before in Saudi Arabia. CASE: We report a 25-year-old ATM male patient presented with a history of sudden onset severe low back pain. Within four hours from the onset of the back pain, he became completely paraplegic with impaired functions of the bowel and urinary bladder sphincter. Furthermore, he lost all modalities of sensory functions in the lower limbs. His examination revealed spastic complete paraplegia with sensory level at T6. Clinical neurological examination revealed normal upper limbs and brain functions. The MRI of the cervico-dorsal spine showed extensive longitudinal hyperintense lesion extending from the upper cervical segments to the lower dorsal segments (extensive longitudinal transverse myelitis). A post-infectious immune-mediated predisposition was highly suspected due to the very high titers of anti-Mycoplasma pneumoniae IgM and IgG that were detected. The immunosuppressant therapy did not improve his paraplegia. A spinal cord biopsy revealed the presence of several Schistosoma mansoni ova surrounded by chronic inflammatory reactions and reactive gliosis. CONCLUSIONS: Both Mycoplasma pneumoniae and Schistosoma mansoni should be investigated in cases with extensive longitudinal ATM.