Ultra-Short Duration Hypothermia Prevents Intracranial Pressure Elevation Following Ischaemic Stroke in Rats

There is a transient increase in intracranial pressure (ICP) 18–24 h after ischaemic stroke in rats, which is prevented by short-duration hypothermia using rapid cooling methods. Clinical trials of long-duration hypothermia have been limited by feasibility and associated complications, which may be avoided by short-duration cooling. Animal studies have cooled faster than is achievable in patients. We aimed to determine whether gradual cooling at a rate of 2°C/h to 33°C or 1°C/h to 34.5°C, with a 30 min duration at target temperatures, prevented ICP elevation and reduced infarct volume in rats. Transient middle cerebral artery occlusion was performed, followed by gradual cooling to target temperature. Hypothermia to 33°C prevented significant ICP elevation (hypothermia ΔICP = 1.56 ± 2.26 mmHg vs normothermia ΔICP = 8.93 ± 4.82 mmHg; p = 0.02) and reduced infarct volume (hypothermia = 46.4 ± 12.3 mm3 vs normothermia = 85.0 ± 17.5 mm3; p = 0.01). Hypothermia to 34.5°C did not significantly prevent ICP elevation or reduce infarct volume. We showed that gradual cooling to 33°C, at cooling rates achievable in patients, had the same ICP preventative effect as traditional rapid cooling methods. This suggests that this paradigm could be translated to prevent delayed ICP rise in stroke patients

Chronic treatment with simvastatin affects cannabinoid receptor type 1 and muscarinic receptors type 2/4 in different brain regions among sham and 6-hydroxydopamine lesioned rats

Background: Simvastatin is a hypolipidemic drug belonging to the family of statins. It has been previously reported that simvastatin, among other statins, significantly prevented dopaminergic neurons from degeneration in Parkinsonism in vivo model. Objectives: It has been well documented that there are close interactions among the cannabinoid, muscarinic, and dopaminergic systems. This study aimed to explore whether chronic simvastatin treatment prevented any perturbations in autoradiography binding expression of Cannabinoid receptor type 1 (CB1) and Muscarinic receptors type 2/4 (M2/4) from 6-hydroxydopamine (6-OHDA) lesioning in the medial forebrain bundle of rat brains. Method: Male Sprague Dawley rats (5 to 8 per group) were randomized for receiving saline or for the 6-OHDA-lesioned Parkinsonian model. Before surgery, rats were pretreated with 1mg/kg/day simvastatin, or 10 mg/kg/day simvastatin, or saline for 5 days (sham group), and the same treatment for each group was continued for 3 weeks after surgery. Simvastatin or saline was administered via an oral gavage daily. Quantitative autoradiography was employed to investigate the binding density of CB1 receptors using [3H] SR141716A and M2/4 receptors using [3H] AF-DX 384 in rat brain sections. Results: Rats given only 6-OHDA lesion significantly up-regulated [3H] AF-DX 384 receptor binding levels in all brain regions when compared to the sham rat group (p\u3c0.05). 6-OHDA lesioned rats treated with simvastatin at 1 mg/kg/day significantly reversed these elevations only in the prefrontal cortex, nucleus accumbens, and substantia nigra (p\u3c0.05). 6-OHDA lesioned only rats significantly down-regulated [3H] SR141716A receptor binding levels when compared to the sham rat group in all brain regions examined (p\u3c0.05). 6-OHDA lesioned rats with chronic simvastatin treatment at 10 mg/kg/day significantly elevated binding levels compared to the rats given only 6-OHDA lesion in all brain regions examined (p\u3c0.05). Treatment in 6-OHDA lesioned rats with 1 mg/kg/day of simvastatin also significantly elevated binding levels compared to rats given 6-OHDA lesions alone, in the substantia nigra and hippocampus (p\u3c0.05). Conclusions: Chronic simvastatin treatment restored CB1 receptor binding to normal levels, whereas M2/4 receptor binding density was only restored in a few regions compared to rats that received the 6-OHDA lesion. These findings contribute to a better understanding of the critical role of simvastatin in treating neuropsychological dysfunctions such as PD, potentially via CB1 and M2/4 receptors

Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages

Spinal muscular atrophy (SMA) is an autosomal recessive disease linked to survival motor neuron (SMN) protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in synergy with other cell populations. We took advantage of this new system to first test the effect of motor neuron or muscle-specific smn1 silencing. Anti-smn1 miRNA expression in motor neurons, but not in muscles, reproduced SMA hallmarks, including abnormal motor neuron development, poor motor function and premature death. Interestingly, smn1 knockdown in motor neurons also induced severe late-onset phenotypes including scoliosis-like body deformities, weight loss, muscle atrophy and, seen for the first time in zebrafish, reduction in the number of motor neurons, indicating motor neuron degeneration. Taken together, we have developed a new transgenic system allowing spatio-temporal control of smn1 expression in zebrafish, and using this model, we have demonstrated that smn1 silencing in motor neurons alone is sufficient to reproduce SMA hallmarks in zebrafish. It is noteworthy that this research is going beyond SMA as this versatile gene-silencing transgenic system can be used to knockdown any genes of interest, filling the gap in the zebrafish genetic toolbox and opening new avenues to study gene functions in this organism

Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains

Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [3H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all pb0.05); however 10 mg/kg/day simvastatin increased H1 receptor density only in the medial amygdaloid nucleus (Mep) (pb0.05), but had no significant effect in other regions examined. The 6-OHDA lesion did not alter H1 receptor binding density in most brain areas, except a trend decrease in the hippocampus (p=0.07) and a trend increase in the cingulate cortex (p=0.06). These results suggested that simvastatin has different effects on the H1 receptors in different rat brain regions depending on the doses. Therefore, simvastatin can modulate histaminergic neurotransmission in the brain, and support the role of H1 receptors in psychoneurological disorders

Reversal effect of simvastatin on the decrease in cannabinoid receptor 1 density in 6-hydroxydopamine lesioned rat brains

Aims: Cannabinoid 1(CB1) receptors are closely correlated to the dopaminergic system and involved in cognitive function. Since statins have been used to regulate the progression of Parkinson\u27s disease (PD) via its anti-inflammation and neuroprotective effects, we asked if statins affect the CB1 receptors in the 6-hydroxydopamine (6-OHDA) lesioned rat. Methods: The PD rat model was established by injecting 6-OHDA into the unilateral medial forebrain bundle; while rats were orally pre-treated with simvastatin (1 or 10 mg/kg/day), or saline for 5 days before surgery, and the same treatments for each group were continued for 3 weeks post-surgery. [3H] SR141716A binding autoradiography was adopted to investigate the alterations in CB1 receptor density in the brains. Findings: The 6-OHDA induced a remarkable downregulation of CB1 receptor density in the prefrontal cortex, caudate putamen, nucleus accumbens, cingulate cortex, hippocampus, and substantia nigra; while simvastatin (10 mg/kg/day) significantly ameliorated this downregulation in those regions. Furthermore, simvastatin (1 mg/kg/day) reversed the 6-OHDA-induced downregulation of CB1 receptors in the substantia nigra and hippocampus. Simvastatin showed minimal changes in [3H] SR141716A binding in the examined regions in sham rats, but did reveal a significant down-regulation of binding density within the striatum, prefrontal cortex and substantia nigra. Significance: Alterations in the [3H] SR141716A binding in the examined brain areas may represent the specific regions that mediate motor and cognitive dysfunctions in PD via the endocannabinoid system. Our data suggest a critical role of CB1 receptors in treating PD with simvastatin, and implicate CB1 receptors as a potential therapeutic target in the treatment of PD