Traumatic brain injury (TBI) is a complex and multifaceted disorder that has become a significant public health concern worldwide due to its contribution to mortality and morbidity. This condition ...encompasses a spectrum of injuries, including axonal damage, contusions, edema, and hemorrhage. Unfortunately, specific effective therapeutic interventions to improve patient outcomes following TBI are currently lacking. Various experimental animal models have been developed to mimic TBI and evaluate potential therapeutic agents to address this issue. These models are designed to recapitulate different biomarkers and mechanisms involved in TBI. However, due to the heterogeneous nature of clinical TBI, no single experimental animal model can effectively mimic all aspects of human TBI. Accurate emulation of clinical TBI mechanisms is also tricky due to ethical considerations. Therefore, the continued study of TBI mechanisms and biomarkers, of the duration and severity of brain injury, treatment strategies, and animal model optimization is necessary. This review focuses on the pathophysiology of TBI, available experimental TBI animal models, and the range of biomarkers and detection methods for TBI. Overall, this review highlights the need for further research to improve patient outcomes and reduce the global burden of TBI.
Antiretroviral treatments have notably extended the lives of individuals with HIV and reduced the occurrence of comorbidities, including ocular manifestations. The involvement of endoplasmic ...reticulum (ER) stress in HIV-1 pathogenesis raises questions about its correlation with cellular senescence or its role in initiating senescent traits. This study investigated how ER stress and dysregulated autophagy impact cellular senescence triggered by HIV-1 Tat in the MIO-M1 cell line (human Müller glial cells). Cells exposed to HIV-1 Tat exhibited increased vimentin expression combined with markers of ER stress (BiP, p-eIF2α), autophagy (LC3, Beclin-1, p62), and the senescence marker p21 compared to control cells. Western blotting and staining techniques like SA-β-gal were employed to examine these markers. Additionally, treatments with ER stress inhibitor 4-PBA before HIV-1 Tat exposure led to a decreased expression of ER stress, senescence, and autophagy markers. Conversely, pre-treatment with the autophagy inhibitor 3-MA resulted in reduced autophagy and senescence markers but did not alter ER stress markers compared to control cells. The findings suggest a link between ER stress, dysregulated autophagy, and the initiation of a senescence phenotype in MIO-M1 cells induced by HIV-1 Tat exposure.
NeuroHIV affects approximately 30–60% of people living with HIV-1 (PLWH) and is characterized by varying degrees of cognitive impairments, presenting a multifaceted challenge, the underlying cause of ...which is chronic, low-level neuroinflammation. Such smoldering neuroinflammation is likely an outcome of lifelong reliance on antiretrovirals coupled with residual virus replication in the brains of PLWH. Despite advancements in antiretroviral therapeutics, our understanding of the molecular mechanism(s) driving inflammatory processes in the brain remains limited. Recent times have seen the emergence of non-coding RNAs (ncRNAs) as critical regulators of gene expression, underlying the neuroinflammatory processes in HIV infection, NeuroHIV, and their associated comorbidities. This review explores the role of various classes of ncRNAs and their regulatory functions implicated in HIV infection, neuropathogenesis, and related conditions. The dysregulated expression of ncRNAs is known to exacerbate the neuroinflammatory responses, thus contributing to neurocognitive impairments in PLWH. This review also discusses the diagnostic and therapeutic potential of ncRNAs in HIV infection and its comorbidities, suggesting their utility as non-invasive biomarkers and targets for modulating neuroinflammatory pathways. Understanding these regulatory roles could pave the way for novel diagnostic strategies and therapeutic interventions in the context of HIV and its comorbidities.
Hypoxia is a state in which the body or a specific part of the body is deprived of adequate oxygen supply at the tissue level. Sojourners involved in different activities at high altitudes (> 2500 m) ...face hypobaric hypoxia (HH) due to low oxygen in the atmosphere. HH is an example of generalized hypoxia, where the homeostasis of the entire body of an organism is affected and results in neurochemical changes. It is known that lower O
2
levels affect catecholamines (CA), severely impairing cognitive and locomotor behavior. However, there is less evidence on the effect of HH-mediated alteration in brain Tetrahydrobiopterin (BH4) levels and its role in neurobehavioral impairments. Hence, this study aimed to shed light on the effect of acute HH on CA and BH4 levels with its neurobehavioral impact on Wistar rat models. After HH exposure, significant alteration of the CA levels in the discrete brain regions,
viz.
, frontal cortex, hippocampus, midbrain, and cerebellum was observed. HH exposure significantly reduced spontaneous motor activity, motor coordination, and spatial memory. The present study suggests that the HH-induced behavioral changes might be related to the alteration of the expression pattern of CA and BH4-related genes and proteins in different rat brain regions. Overall, this study provides novel insights into the role of BH4 and CA in HH-induced neurobehavioral impairments.
Graphical Abstract
Human immunodeficiency virus (HIV) and drug abuse are intertwined epidemics, leading to compromised adherence to combined antiretroviral therapy (cART) and exacerbation of NeuroHIV. As opioid abuse ...causes increased viral replication and load, leading to a further compromised immune system in people living with HIV (PLWH), it is paramount to address this comorbidity to reduce the NeuroHIV pathogenesis. Non-human primates are well-suited models to study mechanisms involved in HIV neuropathogenesis and provide a better understanding of the underlying mechanisms involved in the comorbidity of HIV and drug abuse, leading to the development of more effective treatments for PLWH. Additionally, using broader behavioral tests in these models can mimic mild NeuroHIV and aid in studying other neurocognitive diseases without encephalitis. The simian immunodeficiency virus (SIV)–infected rhesus macaque model is instrumental in studying the effects of opioid abuse on PLWH due to its similarity to HIV infection. The review highlights the importance of using non-human primate models to study the comorbidity of opioid abuse and HIV infection. It also emphasizes the need to consider modifiable risk factors such as gut homeostasis and pulmonary pathogenesis associated with SIV infection and opioid abuse in this model. Moreover, the review suggests that these non-human primate models can also be used in developing effective treatment strategies for NeuroHIV and opioid addiction. Therefore, non-human primate models can significantly contribute to understanding the complex interplay between HIV infection, opioid abuse, and associated comorbidities.
Graphical Abstract
Motion sickness (MS) occurs due to contradicting vestibular and visual inputs to the brain causing nausea and vomiting. Antidopaminergic drugs being effective in reducing MS create a path for ...effective therapy against MS by regulating dopamine levels. We aimed to evaluate the role of the striatum and brainstem dopamine and dopamine D2 receptor (DRD2) in MS and the efficacy of menthol (MNT) to modulate dopamine and DRD2 in vitro and in vivo for possible amelioration of MS. Evaluation of efficacy of MNT to inhibit dopamine release from PC12 cells and anti‐MS efficacy in BALB/c mice model was performed. Dopamine, DRD2 expression in PC12 cells, mice striatum, and brainstem were detected using HPLC‐ECD, RT‐PCR, and Western blot analysis, respectively. DRD2 expression increased in calcium ionophore‐treated PC12 cells compared with control cells. Pretreatment with 50 μg/ml menthol decreased dopamine and DRD2 expression. Similarly, dopamine and DRD2 levels in mice striatum and brainstem of MS group (rotation induced) increased significantly compared with control group NC (no rotation). Pretreatment with menthol at 50 mg/kg concentration (rotation induced) showed decreased dopamine and DRD2 expression, thus indicating ameliorative effect on MS. Hence, we suggest that increased striatum and brainstem dopamine and DRD2 levels might lead to MS symptoms, and menthol could be used as a potent herbal alternative medicine for MS.
Practical applications
Antidopaminergic drugs being effective in reducing motion sickness (MS) creates a path for effective therapy against MS by regulating dopamine levels.
Increased striatum and brainstem dopamine and Dopamine D2 receptor (DRD2) levels might lead to the MS symptoms induced by rotation stimulation in mice model.
Menthol showed a prophylactic effect on rotation‐induced MS by reducing striatal and brainstem dopamine levels, DRD2 mRNA, and protein expression.
Menthol could be used as an herbal alternative to antidopaminergics to minimize the associated adverse effects.
Motion sickness (MS) is the visceral discomfort caused due to contradicting visual and vestibular inputs to the brain leading to nausea and vomiting. Sensory conflict theory which proves histamine ...elevations as the primary reason for MS provides a path for an effective pharmaco-therapy. We aimed to evaluate the anti-MS effect of hesperidin (HSP) by modulating histamine and histamine receptor H1 (HRH1) expression. The inhibitory effect of HSP on histamine release was studied in KU812 cells treated with 10 µM calcium ionophore. The in vivo anti-MS effect of HSP was evaluated in Balb/c mice. Thirty six mice were divided into six groups namely, normal control (NC, no rotation), hesperidin at 80 mg/kg body weight control (HSP80, no rotation), motion sickness (MS, rotation induced), dimenhydrinate (Standard drug) at 20 mg/kg body weight + rotation (STD + MS), hesperidin at 40 mg/kg body weight + rotation (HSP40 + MS) and hesperidin at 80 mg/kg body weight + rotation (HSP80 + MS). Hypothalamus and brainstem samples were analysed for histamine levels and HRH1 expression by RT-PCR, Western blot and immunohistochemistry analysis. Calcium ionophore treated KU812 cells significantly increased histamine release when compared to control cells. Pre-treatment with HSP inhibited histamine, HRH1 mRNA and protein expression. Histamine, HRH1 mRNA and protein expression in hypothalamus and brainstem samples of MS group increased significantly when compared to the NC group. Pre-treatment with HSP significantly reduced histamine, HRH1 mRNA and protein expression. Thus, indicating that HSP has a potent anti- MS effect by decreasing the elevated levels of histamine, HRH1 mRNA and protein expression in hypothalamus and brainstem regions.
Terminalia arjuna
is well known for its health benefits. It is used as a traditional medicine to cure many disease conditions. In the present study, the authors have evaluated the cardioprotective ...potential of
T. arjuna
extract (TAE) against isoproterenol (ISO)-induced cardiac stress in male Wistar albino rats. TAE 50 and 75 mg/kg body weight significantly (
p
< 0.01) protected rats against ISO (85 mg/kg body weight)-induced stress and were evidenced by electrocardiography and serum biomarker enzyme levels. Pretreatment with TAE-protected oxidative stress-induced cardiac stress by decreasing the generation of free radical like ROS, hydroperoxide and nitrite levels. TAE pretreatment retained cardiac rhythm, myocardial membrane integrity and reduced the rate of lipid peroxidation induced by ISO treatment. TAE pretreatment also elevated antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase) and total glutathione levels against ISO-induced cardiac stress. Further, anti-apoptotic effects of TAE were confirmed by immunoblotting studies by alleviating the phosphorylation of JNK, c-jun and also by regulating protein expressions of Bax, Bcl
2
and iNOS levels in myocardium. Overall results suggest that the TAE extract exhibits antioxidant and anti-apoptotic defense mechanisms against ISO-induced cardiac stress in Wistar albino rats.
