Beam narrowing test: a motor index of post-stroke motor evaluation in an aged rat model of cerebral ischemia.

Each year, 15 million people worldwide suffer from strokes. Consequently, researchers face increasing pressure to develop reliable behavioural tests for assessing functional recovery after a stroke. Our aim was to establish a new motor performance index that can be used to evaluate post-stroke recovery in both young and aged animals. Furthermore, we validate the proposed procedure and recommend the necessary number of animals for experimental stroke studies. Young (n = 20) and aged (n = 27) Sprague-Dawley rats were randomly assigned to receive either sham or stroke surgery. The newly proposed performance index was calculated for the post-stroke acute, subacute and chronic phases. The advantage of using our test over current tests lies in the fact that the newly proposed motor index test evaluates not only the performance of the unaffected side in comparison to the affected one but also assesses overall performance by taking into account speed and coordination. Moreover, it reduces the number of animals needed to achieve a statistical power of 80%. This aspect is particularly crucial when studying aged rodents. Our approach can be used to monitor and assess the effectiveness of stroke therapies in experimental models using aged animals.

Stem Cell Treatments in Preclinical Relevant Stroke Models.

Since stroke has limited treatment options, an active search for new therapeutic approaches is required. Initial excitement of using cell-based therapies to stimulate recovery processes in the ischemic brain turned into a more measured perspective, acknowledging obstacles related to the unfavorable environments associated in part with aging. Given the predominance of stroke in older populations, evaluating the effectiveness of cell therapies in aged brain environments is essential and clinically relevant. Despite a common perception of the aged brain being resistant to regeneration, recent research with neural precursor cells and bone marrow-derived mesenchymal stem cells indicates that cell-based therapy can promote plasticity and remodeling in the aged rat brain. However, significant differences in the aged brain compared to the young brain, such as expedited progression of ischemic injury to brain infarction, decreased rate of endogenous neurogenesis, and delayed onset of neurological recovery, must be noted. The effectiveness of cell-based therapies may further be connected to age-related comorbidities such as diabetes or hyperlipidemia, potentially leading to maladaptive or impaired brain remodeling. These age-related factors need careful consideration in the clinical application of restorative therapies for stroke.

Neuroglia Cells Transcriptomic in Brain Development, Aging and Neurodegenerative Diseases.

Glia cells are essential for brain functioning during development, aging and disease. However, the role of astroglia plays during brain development is quite different from the role played in the adult lesioned brain. Therefore, a deeper understanding of pathomechanisms underlying astroglia activity in the aging brain and cerebrovascular diseases is essential to guide the development of new therapeutic strategies. To this end, this review provides a comparison between the transcriptomic activity of astroglia cells during development, aging and neurodegenerative diseases, including cerebral ischemia. During fetal brain development, astrocytes and microglia often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, and synaptic pruning. In the adult brain astrocytes are a critical player in the synapse remodeling by mediating synapse elimination while microglia activity has been associated with changes in synaptic plasticity and remove cell debris by constantly sensing the environment. However, in the lesioned brain astrocytes proliferate and play essential functions with regard to energy supply to the neurons, neurotransmission and buildup of a protective scar isolating the lesion site from the surroundings. Inflammation, neurodegeneration, or loss of brain homeostasis induce changes in microglia gene expression, morphology, and function, generally referred to as "primed" microglia. These changes in gene expression are characterized by an enrichment of phagosome, lysosome, and antigen presentation signaling pathways and is associated with an up-regulation of genes encoding cell surface receptors. In addition, primed microglia are characterized by upregulation of a network of genes in response to interferon gamma. Conclusion. A comparison of astroglia cells transcriptomic activity during brain development, aging and neurodegenerative disorders might provide us with new therapeutic strategies with which to protect the aging brain and improve clinical outcome.

Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats.

The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia. Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after MCAO. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze) but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit. Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the gene that were unique to ES, we noted increases in the expression of seizure related 6 homolog like which is one of the physiological substrate of the ß-secretase BACE1 involved in the pathophysiology of the Alzheimer's disease and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus.

Toxicity and health impact of nanoparticles. Basic biology and clinical perspective.

Stroke has limited restorative treatment options. In search of new therapeutic strategies for the ischemic brain, cell-based therapies offered new hope, which has been, in the meanwhile, converted into a more realistic approach recognizing difficulties related to unfavorable environments causing low survival rates of transplanted neuronal precursors. Stem cell therapies are based on the transplantation of neuronal precursor cells (NPCs), adult stem cells propagated in cell culture or inducible pluripotent cells (iPSCs) obtained from patients and trans-differentiated into neural cells. Of these, autologous iPSCs have the advantage to be used in stroke patients because they do not raise ethical concerns and the risk of graft rejection is low. However, the use of stem cells for stroke therapy in humans has to take into account many factors including, dosage, route of administration, toxicity and side effects. For example, nanoparticles (NPs) may increase the efficacy of drugs and therapeutic cells delivery to the diseased brain. Medication dosages are generally determined by clinical trials done in relatively young, healthy people. However, in vivo and clinical data evaluating the toxic effects of NPs on neural cells are still scarce especially in the aged brain, which has a decreased homeostatic capacity and a reduced ability to cope with internal and environmental stress, as compared to the young brain. Previous studies in rodents indicate that aging along with neurodegenerative diseases may promote a proinflammatory state and leads to the development of gliosis in the aged brains. On the other hand, the nonspecific interaction between the shell of NPs and brain proteins leads to the adsorption of opsonins on their surface, forming the so-called "corona", thereby becoming ideal candidates to attract phagocytic microglia resulting in NPs engulfment and thus exacerbating neuronal death. Therefore, when designing NPs for clinical use, it should be considered that their systemic administration is associated with potential risks, especially in the aged subjects. Recently, NPs have been shown in recent years to play a crucial role in cell signaling processes involved in stroke recovery. Extracellular vesicles (EVs) are secreted by virtually all type of cells in the body and have been shown to reflect the physiological and metabolic status of the host cells. Thus, understanding the disease-specific contents of EVs would enable the discovery of novel predictive biomarkers.