RESUMO
Subarachnoid hemorrhage (SAH) represents a considerable health problem. To date, limited therapeutic options are available. In order to develop effective therapeutic strategies for SAH, the mechanisms involved in SAH brain damage should be fully explored. Here we review the mechanisms of SAH brain damage induced by the experimental endovascular puncture model. We have included a description of similarities and distinctions between experimental SAH in animals and human SAH pathology. Moreover, several novel treatment options to diminish SAH brain damage are discussed.SAH is accompanied by cerebral inflammation as demonstrated by an influx of inflammatory cells into the cerebral parenchyma, upregulation of inflammatory transcriptional pathways and increased expression of cytokines and chemokines. Additionally, various cell death pathways including cerebral apoptosis, necrosis, necroptosis and autophagy are involved in neuronal damage caused by SAH.Treatment strategies aiming at inhibition of inflammatory or cell death pathways demonstrate the importance of these mechanisms for survival after experimental SAH. Moreover, neuroregenerative therapies using stem cells are discussed as a possible strategy to repair the brain after SAH since this therapy may extend the window of treatment considerably. We propose the endovascular puncture model as a suitable animal model which resembles the human pathology of SAH and which could be applied to investigate novel therapeutic therapies to combat this debilitating insult.
Assuntos
Lesões Encefálicas/etiologia , Punções/efeitos adversos , Hemorragia Subaracnóidea/etiologia , Animais , Apoptose , Lesões Encefálicas/terapia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Transdução de Sinais , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/terapiaRESUMO
The existence of sexual dysfunctions in men, including premature and retarded ejaculation poses challenges to develop translational models in rats that may help in improving treatment and delineate the neural mechanisms of action. Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When large populations of male rats are tested on sexual activity during four successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes may help to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. Further unravelling of sexual endophenotypes may benefit from the use of chromosomal substitution strains in mice that enable the localization of relevant chromosomal areas and genes involved in ejaculation processes. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation.
Assuntos
Disfunções Sexuais Fisiológicas/tratamento farmacológico , Disfunções Sexuais Fisiológicas/genética , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Disfunções Sexuais Psicogênicas/genética , Animais , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Ejaculação/efeitos dos fármacos , Feminino , Humanos , Masculino , Serotonina/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/induzido quimicamenteRESUMO
Subarachnoid hemorrhage (SAH) represents a major health problem in Western society due to high mortality and morbidity, and the relative young age of patients. Currently, efficacious therapeutic options are very limited. Mesenchymal stem cell (MSC) administration has been shown to improve functional outcome and lesion size in experimental models of stroke and neonatal hypoxic-ischemic brain injury. Here, we studied the therapeutic potential of intranasally administered bone marrow-derived MSCs relatively late postinsult using a rat endovascular puncture model for SAH. Six days after induction of SAH, rats were treated with MSCs or vehicle through nasal administration. Intranasal MSC treatment significantly improved sensorimotor and mechanosensory function at 21 days after SAH. Gray and white matter loss was significantly reduced by MSC treatment and the number of NeuN+ neurons around the lesion increased due to MSC treatment. Moreover, intranasal MSC administration led to a sharp decrease in SAH-induced activation of astrocytes and microglia/macrophages in the lesioned hemisphere, especially of M2-like (CD206+) microglia/macrophages. Interestingly, MSC administration also decreased SAH-induced depression-like behavior in association with a restoration of tyrosine hydroxylase expression in the substantia nigra and striatum. We show here for the first time that intranasal MSC administration reverses the devastating consequences of SAH, including regeneration of the cerebral lesion, functional recovery, and treatment of comorbid depression-like behavior.
Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Cavidade Nasal , Hemorragia Subaracnóidea/terapia , Animais , Células Cultivadas , Corpo Estriado/citologia , Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Substância Negra/citologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Subarachnoid hemorrhage (SAH) represents a considerable health problem with an incidence of 6-7 per 100.000 individuals per year in Western society. We investigated the long-term consequences of SAH on behavior, neuroinflammation and gray- and white-matter damage using an endovascular puncture model in Wistar rats. Rats were divided into a mild or severe SAH group based on their acute neurological score at 24 h post-SAH. The degree of hemorrhage determined in post-mortem brains at 48 h strongly correlated with the acute neurological score. Severe SAH induced increased TNF-α, IL-1ß, IL-10, MCP-1, MIP2, CINC-1 mRNA expression and cortical neutrophil influx at 48 h post-insult. Neuroinflammation after SAH was very long-lasting and still present at day 21 as determined by Iba-1 staining (microglia/macrophages) and GFAP (astrocytes). Long-term neuroinflammation was strongly associated with the degree of severity of SAH. Cerebral damage to gray- and white-matter was visualized by immunohistochemistry for MAP2 and MBP at 21 days after SAH. Severe SAH induced significant gray- and white-matter damage. MAP2 loss at day 21 correlated significantly with the acute neurological score determined at 24 h post-SAH. Sensorimotor behavior, determined by the adhesive removal task and von Frey test, was affected after severe SAH at day 21. In conclusion, we are the first to show that SAH induces ongoing cortical inflammation. Moreover, SAH induces mainly cortical long-term brain damage, which is associated with long-term sensorimotor damage.