Long-term modification of gut microbiota by broad-spectrum antibiotics improves stroke outcome in rats.

BACKGROUND: The brain-gut axis is a major regulator of the central nervous system. We investigated the effects of treatment with broad-spectrum antibiotics on gut and brain inflammation, infarct size and long-term behavioral outcome after cerebral ischemia in rats. METHODS: Rats were treated with broad-spectrum antibiotics (ampicillin, vancomycin, ciprofloxacin, meropenem and metronidazole) for 4 weeks before the endothelin-1 induced ischemia. Treatment continued for 2 weeks until the end of behavioral testing, which included tapered ledged beam-walking, adhesive label test and cylinder test. Gut microbiome, short-chain fatty acids and cytokine levels were measured together with an assessment of infarct size, neuroinflammation and neurogenesis. RESULTS: The results revealed that the antibiotics exerted a clear impact on the gut microbiota. This was associated with a decrease in systemic and brain cytokine levels, infarct size and apoptosis in the perilesional cortex and improved behavioral outcome. CONCLUSION: Our results highlighted the significant relationship between intestinal microbiota and beneficial neuro-recovery after ischemic stroke.

Forced forelimb use following stroke enhances oligodendrogenesis and functional recovery in the rat.

Forced limb use, which forces the use of the impaired arm following stroke, improves functional recovery. The study was designed to investigate the mechanisms of recovery underlying forced impaired limbuse. Furthermore, forced unimpaired arm use was also performed in order to explore its effect on functional behavior. We hypothesized that forced forelimb use could improve functional recovery in rats that have had an experimentally induced ischemic stroke, through promoting the recruitment and differentiation of the oligodendrocyte progenitor cells (OPCs). Indeed the proliferation of Olig2 and NG2 positive cells, as well as the expression of myelin basic protein (MBP)were increased in the perilesional striatum, whereas quantitative changes of Olig2+ and NG2+ oligodendrocyte progenitor cells was not observed in the subventricular zone. Through comparing rats forced to rely on affected or unaffected forelimb, the results demonstrated that forced impaired limb use boosted functional recovery. At the same time forced unimpaired limb use deteriorated limb movement of injured side. In addition, the expression of NogoA is reduced, when the injured limb was used more, suggesting that it played a role in the repair of white matter.

Activation of GABAA receptors enhances the behavioral recovery but not axonal sprouting in ischemic rats.

BACKGROUND: GABAA receptors modulate the behavioral recovery encountered in both experimental animals and patients with ischemic injury, possibly through promoting structural plasticity. We hypothesized that activation of GABAA receptors would regulate axonal growth, which in turn would improve the behavioral recovery in ischemic rats. OBJECTIVE: To investigate the effects of muscimol on axonal growth, synaptic plasticity and behavioral performance in rats after a focal ischemia induced by endothelin-1 (ET-1). METHODS: Focal ischemic infarct was induced by ET-1. The rats were randomly divided into 3 groups: sham-operated group, ischemic group, ischemic+muscimol group. The muscimol infusion into contralateral cortex started on post-operative day 7 continuing until day 21. Biotinylated dextran amine was injected on post-operative day 14 into the contralesional motor cortex to trace the crossing corticospinal tract fibers. The expression levels of growth inhibitors, Nogo receptor, NogoA, RhoA, and Rho-associated kinase were measured in the peri-infarct cortex. The expressions of vGlut-1 and postsynaptic density-95 were measured by immunohistochemistry and Western blot in the denervated spinal cord. The behavioral recovery was evaluated by sensorimotor tests on post-operative days 32-34. RESULTS: Treatment with the specific GABAA receptors agonist, muscimol, did not increase axonal growth into the denervated hemispheres and spinal cord after stroke. However, the activation of GABAA receptors partially improved the rats' behavioral performance after the ET-1-induced stroke. CONCLUSIONS: Our study revealed that infusion of muscimol into the contralateral motor cortex during the repair stage could partially improve the behavioral performances without promoting axonal growth from uninjured hemisphere motor cortex to the denervated striatum and spinal cord, nor did it prevent the expression of axonal growth inhibitors in peri-lesioned cortex. More detailed studies will be required to clarify the role of GABAA Rs in regulating the behavioral recovery after a stroke.

Does the Use of Antidepressants Accelerate the Disease Progress in Creutzfeldt-Jakob Disease Patients With Depression? A Case Report and A Systematic Review.

Background: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder characterized by rapidly progressive dementia. Growing evidence suggests that antidepressant usage was associated with dementia. Given the commonality of depression in CJD, it is necessary to investigate the effect of antidepressants on CJD. Methods: First, we report a case of sporadic CJD (sCJD) with depression where the condition worsened rapidly after using a serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant. Second, a systematic literature survey was conducted to investigate the effect of antidepressants on the survival time of sCJD patients with depression. Thirteen cases plus our case were included for qualitative analysis. Twelve subjects were included in the Kaplan-Meier survival and Cox regression analysis. Finally, we provide a postulation of pathophysiological mechanism in CJD. Results: The median survival time of all patients was 6.0 months, of which patients with SNRIs were significantly shorter than those with first-generation antidepressants (2.0 vs. 6.0 months; log rank, P = .008) and relatively shorter than those with nonselective serotonin reuptake inhibitors (SSRIs; 4.0 vs. 6.0 months; log rank, P = .090). In comparison with first-generation antidepressants, the use of SNRIs [hazard ratio (HR), 23.028; 95% confidence interval (CI), 1.401 to 378.461; P = .028] remained independently associated with shorter survival time. Conclusions: The use of antidepressants, especially SNRIs, was associated with a shorter survival time of sCJD patients. The possible changes in neurotransmitters should be emphasized. Scientifically, this study may provide insights into the mechanism of CJD. Clinically, it may contribute to the early diagnosis of CJD.

Targeting strategies for chemotherapy-induced peripheral neuropathy: does gut microbiota play a role?

Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive, often irreversible condition that produces severe neurological deficits. Emerging data suggest that chemotherapy also exerts detrimental effects on gut microbiota composition and intestinal permeability, contributing to dysbiosis and inflammation. Compared with other complications associated with chemotherapy, such as diarrhoea and mucositis, CIPN is of particular concern because it is the most common reason for terminating or suspending treatment. However, specific and effective curative treatment strategies are lacking. In this review, we provide an update on current preclinical and clinical understandings about the role of gut microbiota in CIPN. The gut microbiota serves as an intersection between the microbiome-gut-brain and the neuroimmune-endocrine axis, forming a complex network that can directly or indirectly affect key components involved in the manifestations of CIPN. Herein, we discuss several potential mechanisms within the context of the networks and summarize alterations in gut microbiome induced by chemotherapeutic drugs, providing great potential for researchers to target pathways associated with the gut microbiome and overcome CIPN.