Attenuation of Streptozotocin-Induced Diabetic Neuropathic Allodynia by Flavone Derivative Through Modulation of GABA-ergic Mechanisms and Endogenous Biomarkers.

Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2'MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2'-MeO6MF (1,10, 30, and 100 mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2'-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2'-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40 mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2'-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2'-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2ß2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2'-MeO6MF.

The Effects of the COVID-19 Pandemic on the Pattern of Fractures in Taif City, Saudi Arabia.

BACKGROUND:  The COVID-19 pandemic forced the world to take restricted orders to control the spread of SARS-CoV-2 by limiting and controlling people's movement inside their countries. According to previous studies, the shutdown and quarantine affected orthopedic trauma presentations and patterns in many countries. This study aimed to show the change in the pattern of fractures in Taif City, Saudi Arabia, during the curfew period during the COVID-19 pandemic in 2020 and compare it with the same period in 2019. METHODS:  A retrospective study of all patients with fractures who came to the emergency room and were treated by the orthopedic department at Alhada Armed Forces Hospital, King Abdulaziz Specialist Hospital, and King Faisal Medical Complex, Taif City. During partial and total lockdowns between March 23 and June 21, 2020, Data was collected from this period during September 2023. Demographics, fracture type and site, mechanism of injury, length of admission, if admitted, and the management plan were documented. These fracture cases were compared with those within the same period of March-June from the previous year. All statistical analysis was done using two-tailed tests. RESULTS:  There was a decrease in the number of fractures at the time of quarantine, with 69 cases in the three months of curfew in 2020, compared to 184 cases in the same three months in 2019. There was a significant difference in the anatomical site of fractures between the two years, with decreased radius/ulna fractures (P= 0.035) and foot fractures (P=0.010). Most fractures during the lockdown were due to home accidents, with a significant decrease in motor vehicle accidents (P=0.009). CONCLUSION:  The pattern of fractures in Taif City was affected by the movement restriction during the COVID-19 pandemic. The number of fractures decreased by 62.5% during the quarantine compared with the pre-pandemic period. A significant decrease was noted in the number of hospitalized patients (33%) during the COVID-19 lockdown compared to 65.8% in the pre-pandemic period.

Pharmacological characterization of the antidiabetic drug metformin in atherosclerosis inhibition: A comprehensive insight.

BACKGROUND: Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid-related factor 2 (Nrf2) and Kruppel-like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti-inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin-sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long-term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti-inflammatory effect, may attenuate the development and progression of AS. AIMS: Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. CONCLUSION: In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis.

Blunted Melatonin Circadian Rhythm in Parkinson's Disease: Express Bewilderment.

Melatonin (MTN) is a neuro-hormone released from the pineal gland. MTN secretion is regulated by different neuronal circuits, including the retinohypothalamic tract and suprachiasmatic nucleus (SCN), which are affected by light. MTN is neuroprotective in various neurodegenerative diseases, including Parkinson's disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD.

The functional and molecular roles of p75 neurotrophin receptor (p75NTR) in epilepsy.

Epilepsy is a chronic neurological disorder manifested by recurring unprovoked seizures resulting from an imbalance in the inhibitory and excitatory neurotransmitters in the brain. The process of epileptogenesis involves a complex interplay between the reduction of inhibitory gamma-aminobutyric acid (GABA) and the enhancement of excitatory glutamate. Pro-BDNF/p75NTR expression is augmented in both glial cells and neurons following epileptic seizures and status epileptics (SE). Over-expression of p75NTR is linked with the pathogenesis of epilepsy, and augmentation of pro-BDNF/p75NTR is implicated in the pathogenesis of epilepsy. However, the precise mechanistic function of p75NTR in epilepsy has not been completely elucidated. Therefore, this review aimed to revise the mechanistic pathway of p75NTR in epilepsy.

Roles of p75 neurotrophin receptor (p75NTR) in epilepsy: Epilepsy is a chronic neurological disorder manifested by recurring unprovoked seizures resulting from an imbalance in the inhibitory and excitatory neurotransmitters in the brain. The process of epileptogenesis involves a complex interplay between the reduction of inhibitory gamma-aminobutyric acid (GABA) and the enhancement of excitatory glutamate. Pro-BDNF/p75NTR expression is augmented in both glial cells and neurons following epileptic seizures and status epileptics (SE). Over-expression of p75NTR is linked with the pathogenesis of epilepsy, and augmentation of pro-BDNF/p75NTR is implicated in the pathogenesis of epilepsy. However, the precise mechanistic function of p75NTR in epilepsy has not been completely elucidated.

Therapeutic Potential Effect of Glycogen Synthase Kinase 3 Beta (GSK-3ß) Inhibitors in Parkinson Disease: Exploring an Overlooked Avenue.

Parkinson's disease (PD) is a progressive neurodegenerative disease of the brain due to degeneration of dopaminergic neurons in the substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3ß) is implicated in the pathogenesis of PD. Therefore, the purpose of the present review was to revise the mechanistic role of GSK-3ß in PD neuropathology, and how GSK-3ß inhibitors affect PD neuropathology. GSK-3 is a conserved threonine/serine kinase protein that is intricate in the regulation of cellular anabolic and catabolic pathways by modulating glycogen synthase. Over-expression of GSK-3ß is also interconnected with the development of different neurodegenerative diseases. However, the underlying mechanism of GSK-3ß in PD neuropathology is not fully clarified. Over-expression of GSK-3ß induces the development of PD by triggering mitochondrial dysfunction and oxidative stress in the dopaminergic neurons of the SN. NF-κB and NLRP3 inflammasome are activated in response to dysregulated GSK-3ß in PD leading to progressive neuronal injury. Higher expression of GSK-3ß in the early stages of PD neuropathology might contribute to the reduction of neuroprotective brain-derived neurotrophic factor (BDNF). Thus, GSK-3ß inhibitors may be effective in PD by reducing inflammatory and oxidative stress disorders which are associated with degeneration of dopaminergic in the SN.