The Effects of Vagus Nerve Stimulation on Animal Models of Stroke-Induced Injury: A Systematic Review.

Ischemic stroke is one of the leading causes of death worldwide, and poses a great burden to society and the healthcare system. There have been many recent advances in the treatment of ischemic stroke, which usually results from the interruption of blood flow to a particular part of the brain. Current treatments for ischemic stroke mainly focus on revascularization or reperfusion of cerebral blood flow to the infarcted tissue. Nevertheless, reperfusion injury may exacerbate ischemic injury in patients with stroke. In recent decades, vagus nerve stimulation (VNS) has emerged as an optimistic therapeutic intervention. Accumulating evidence has demonstrated that VNS is a promising treatment for ischemic stroke in various rat models through improved neural function, cognition, and neuronal deficit scores. We thoroughly examined previous evidence from stroke-induced animal studies using VNS as an intervention until June 2022. We concluded that VNS yields stroke treatment potential by improving neurological deficit score, infarct volume, forelimb strength, inflammation, apoptosis, and angiogenesis. This review also discusses potential molecular mechanisms underlying VNS-mediated neuroprotection. This review could help researchers conduct additional translational research on patients with stroke.

Protocol paper: kainic acid excitotoxicity-induced spinal cord injury paraplegia in Sprague-Dawley rats.

BACKGROUND: Excitotoxicity-induced in vivo injury models are vital to reflect the pathophysiological features of acute spinal cord injury (SCI) in humans. The duration and concentration of chemical treatment controls the extent of neuronal cell damage. The extent of injury is explained in relation to locomotor and behavioural activity. Several SCI in vivo methods have been reported and studied extensively, particularly contusion, compression, and transection models. These models depict similar pathophysiology to that in humans but are extremely expensive (contusion) and require expertise (compression). Chemical excitotoxicity-induced SCI models are simple and easy while producing similar clinical manifestations. The kainic acid (KA) excitotoxicity model is a convenient, low-cost, and highly reproducible animal model of SCI in the laboratory. The basic impactor approximately cost between 10,000 and 20,000 USD, while the kainic acid only cost between 300 and 500 USD, which is quite cheap as compared to traditional SCI method. METHODS: In this study, 0.05 mM KA was administered at dose of 10 µL/100 g body weight, at a rate of 10 µL/min, to induce spinal injury by intra-spinal injection between the T12 and T13 thoracic vertebrae. In this protocol, detailed description of a dorsal laminectomy was explained to expose the spinal cord, following intra-spinal kainic acid administration at desired location. The dose, rate and technique to administer kainic acid were explained extensively to reflect a successful paraplegia and spinal cord injury in rats. The postoperative care and complication post injury of paraplegic laboratory animals were also explained, and necessary requirements to overcome these complications were also described to help researcher. RESULTS: This injury model produced impaired hind limb locomotor function with mild seizure. Hence this protocol will help researchers to induce spinal cord injury in laboratories at extremely low cost and also will help to determine the necessary supplies, methods for producing SCI in rats and treatments designed to mitigate post-injury impairment. CONCLUSIONS: Kainic acid intra-spinal injection at the concentration of 0.05 mM, and rate 10 µL/min, is an effective method create spinal injury in rats, however more potent concentrations of kainic acid need to be studied in order to create severe spinal injuries.

Protocol paper: kainic acid excitotoxicity-induced spinal cord injury paraplegia in Sprague-Dawley rats

BACKGROUND: Excitotoxicity-induced in vivo injury models are vital to reflect the pathophysiological features of acute spinal cord injury (SCI) in humans. The duration and concentration of chemical treatment controls the extent of neuronal cell damage. The extent of injury is explained in relation to locomotor and behavioural activity. Several SCI in vivo methods have been reported and studied extensively, particularly contusion, compression, and transection models. These models depict similar pathophysiology to that in humans but are extremely expensive (contusion) and require expertise (compression). Chemical excitotoxicity-induced SCI models are simple and easy while producing similar clinical manifestations. The kainic acid (KA) excitotoxicity model is a convenient, low-cost, and highly reproducible animal model of SCI in the laboratory. The basic impactor approximately cost between 10,000 and 20,000 USD, while the kainic acid only cost between 300 and 500 USD, which is quite cheap as compared to traditional SCI method. METHODS: In this study, 0.05 mM KA was administered at dose of 10 µL/100 g body weight, at a rate of 10 µL/min, to induce spinal injury by intra-spinal injection between the T12 and T13 thoracic vertebrae. In this protocol, detailed description of a dorsal laminectomy was explained to expose the spinal cord, following intra-spinal kainic acid administration at desired location. The dose, rate and technique to administer kainic acid were explained extensively to reflect a successful paraplegia and spinal cord injury in rats. The postoperative care and complication post injury of paraplegic laboratory animals were also explained, and necessary requirements to overcome these complications were also described to help researcher. RESULTS: This injury model produced impaired hind limb locomotor function with mild seizure. Hence this protocol will help researchers to induce spinal cord injury in laboratories at extremely low cost and also will help to determine the necessary supplies, methods for producing SCI in rats and treatments designed to mitigate post-injury impairment. CONCLUSIONS: Kainic acid intra-spinal injection at the concentration of 0.05 mM, and rate 10 µL/min, is an effective method create spinal injury in rats, however more potent concentrations of kainic acid need to be studied in order to create severe spinal injuries.

Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury.

BACKGROUND: Myocardial infarction (MI) reperfusion therapy causes paradoxical cardiac complications. Following restoration of blood flow to infarcted regions, a multitude of inflammatory cells are recruited to the site of injury for tissue repair. Continual progression of cardiac inflammatory responses does, however, lead to adverse cardiac remodeling, inevitably causing heart failure. MAIN BODY: Increasing evidence of the cardioprotective effects of both invasive and non-invasive vagal nerve stimulation (VNS) suggests that these may be feasible methods to treat myocardial ischemia/reperfusion injury via anti-inflammatory regulation. The mechanisms through which auricular VNS controls inflammation are yet to be explored. In this review, we discuss the potential of autonomic nervous system modulation, particularly via the parasympathetic branch, in ameliorating MI. Novel insights are provided about the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages. Acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages polarizes the pro-inflammatory into anti-inflammatory subtypes. Activation of the α7nAChR stimulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This inhibits the secretion of pro-inflammatory cytokines, limiting ischemic injury in the myocardium and initiating efficient reparative mechanisms. We highlight recent developments in the controversial auricular vagal neuro-circuitry and how they may relate to activation of the cholinergic anti-inflammatory pathway. CONCLUSION: Emerging published data suggest that auricular VNS is an inexpensive healthcare modality, mediating the dynamic balance between pro- and anti-inflammatory responses in cardiac macrophages and ameliorating cardiac ischemia/reperfusion injury.

Hyperbaric oxygen therapy increases insulin sensitivity in overweight men with and without type 2 diabetes.

AIMS: The onset of insulin resistance is an important metabolic event in the development of type 2 diabetes. For patients with type 2 diabetes, we recently showed that peripheral insulin sensitivity was increased during hyperbaric oxygen treatment (HBOT). This study aims to investigate whether this occurs in a non-patient population with and without type 2 diabetes, along with the mechanism of this effect. METHODS: Overweight and obese male participants were recruited from the community, 11 without and eight with type 2 diabetes. Insulin sensitivity was measured by the glucose infusion rate (GIR) during a hyperinsulinaemic euglycaemic clamp (80 mU·m⁻²·min⁻¹) at baseline and during the third HBOT session. Monocyte chemo-attractant protein-1 (MCP-1), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured in fasting serum and adipose tissue samples taken for their gene expression at baseline and immediately following four HBOT sessions. Additional fasting serum samples were collected during the first HBOT at 0, 60 and 120 minutes, and 24-hours after the last HBOT. RESULTS: In response to HBOT, GIR was increased by 29±32% in those without (n=10, P=0.01), and by 57±66% in those with type 2 diabetes (n=7, P=0.04). This increase was maintained for 30 minutes post HBOT. Reduced MCP-1 and TNF-α were observed after HBOT, whereas IL-6 was increased only in individuals without diabetes and this correlated with the increase in insulin sensitivity (r²=0.72, P=0.004). CONCLUSIONS: Peripheral insulin sensitivity was increased following HBOT in overweight or obese males with and without type 2 diabetes; this increase was maintained for at least 30 minutes post HBOT. Changes in inflammatory cytokines may partly explain this effect.