Exercise-induced motor improvement after complete spinal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic markers

<p>Abstract</p> <p>Background</p> <p>It has been postulated that exercise-induced activation of brain-derived neurotrophic factor (BDNF) may account for improvement of stepping ability in animals after complete spinal cord transection. As we have shown previously, treadmill locomotor exercise leads to up-regulation of BDNF protein and mRNA in the entire neuronal network of intact spinal cord. The questions arise: (i) how the treadmill locomotor training, supplemented with tail stimulation, affects the expression of molecular correlates of synaptic plasticity in spinal rats, and (ii) if a response is related to BDNF protein level and distribution.</p> <p>We investigated the effect of training in rats spinalized at low thoracic segments on the level and distribution of BDNF immunoreactivity (IR) in ventral quadrants of the lumbar segments, in conjunction with markers of presynaptic terminals, synaptophysin and synaptic zinc.</p> <p>Results</p> <p>Training improved hindlimb stepping in spinal animals evaluated with modified Basso-Beattie-Bresnahan scale. Grades of spinal trained animals ranged between 5 and 11, whereas those of spinal were between 2 and 4. Functional improvement was associated with changes in presynaptic markers and BDNF distribution. Six weeks after transection, synaptophysin IR was reduced by 18% around the large neurons of lamina IX and training elevated its expression by over 30%. The level of synaptic zinc staining in the ventral horn was unaltered, whereas in ventral funiculi it was decreased by 26% postlesion and tended to normalize after the training. Overall BDNF IR levels in the ventral horn, which were higher by 22% postlesion, were unchanged after the training. However, training modified distribution of BDNF in the processes with its predominance in the longer and thicker ones. It also caused selective up-regulation of BDNF in two classes of cells (soma ranging between 100-400 μm²and over 1000 μm²) of the ventrolateral and laterodorsal motor nuclei.</p> <p>Conclusion</p> <p>Our results show that it is not BDNF deficit that determines lack of functional improvement in spinal animals. They indicate selectivity of up-regulation of BDNF in distinct subpopulations of cells in the motor nuclei which leads to changes of innervation targeting motoneurons, tuned up by locomotor activity as indicated by a region-specific increase of presynaptic markers.</p

Cellular therapies and neural precursors in the adult brain

Współczesna medycyna w miarę dobrze radzi sobie z leczeniem wielu chorób nabytych i wrodzonych, jednak skuteczna i trwała naprawa większości zaburzeń ośrodkowego układu nerwowego wciąż pozostaje poza naszymi możliwościami. Dlatego prowadzi się intensywne badania podstawowe i przedkliniczne, które umożliwiłyby lepsze poznanie przyczyn takich ograniczeń oraz dawały możliwość opracowania nowych terapii zaburzeń neurodegeneracyjnych, udarów, urazowego uszkodzenia mózgu i rdzenia kręgowego oraz innych chorób. Jednym z bardziej obiecujących kierunków są terapie komórkowe z wykorzystaniem własnych, endogennych mechanizmów naprawczych, innym kierunkiem jest zastosowanie nowych, egzogennych komórek. W pracy przedstawiono ogólne przyczyny trudności naprawy uszkodzeń mózgu, a następnie zjawiska powstawania nowych neuronów w mózgu dorosłych zwierząt i ludzi w sytuacji fizjologicznej oraz w sytuacji uszkodzenia mózgu. Omówiono niektóre przykłady wykorzystania prekursorów w strategiach naprawczych. W ostatniej części pracy przedstawiono wybrane terapie z zastosowaniem przeszczepów innych, mniej typowych prekursorów neuronów i gleju obecnych w mózgu w naprawie uszkodzeń ośrodkowego układu nerwowego.Modern medicine can treat relatively well many acquired and congenital diseases but still an effective and durable repair of the most of central nervous system disorders is beyond our capabilities. Therefore, comprehensive basic and preclinical studies are being carried out which would allow a better understanding of the reasons of these limits. They can potentially provide new strategies for neurodegenerative disorders, stroke, traumatic brain and spinal cord injury, and other diseases. Some of the most promising approaches are cell therapies with the use of endogenous repair mechanisms, but also another direction might be provided with new exogenous cell therapies. The article outlines the general reasons for the difficulties in the brain repair and discusses the phenomenon of new neurons in the brain of adult animals and humans, in the context of physiology and the brain injury. Promising strategies with neural precursors in the Central Nervous System repair are presented. Finally, promising state-of-the-art approaches with not typical cell subtypes of neuronal and glial precursors from the brain transplantation therapies are presented

Impaired Generation of Transit-Amplifying Progenitors in the Adult Subventricular Zone of Cyclin D2 Knockout Mice

In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ&mdash;the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases

Regenerative Drug Discovery Using Ear Pinna Punch Wound Model in Mice

The ear pinna is a complex tissue consisting of the dermis, cartilage, muscles, vessels, and nerves. Ear pinna healing is a model of regeneration in mammals. In some mammals, including rabbits, punch wounds in the ear pinna close spontaneously; in common-use laboratory mice, they remain for life. Agents inducing ear pinna healing are potential regenerative drugs. We tested the effects of selected bioactive agents on 2 mm ear pinna wound closure in BALB/c mice. Our previous research demonstrated that a DNA methyltransferase inhibitor, zebularine, remarkably induced ear pinna regeneration. Although experiments with two other demethylating agents, RG108 and hydralazine, were unsuccessful, a histone deacetylase inhibitor, valproic acid, was another epigenetic agent found to increase ear hole closure. In addition, we identified a pro-regenerative activity of 4-ketoretinoic acid, a retinoic acid metabolite. Attempts to counteract the regenerative effects of the demethylating agent zebularine, with folates as methyl donors, failed. Surprisingly, a high dose of methionine, another methyl donor, promoted ear hole closure. Moreover, we showed that the regenerated areas of ear pinna were supplied with nerve fibre networks and blood vessels. The ear punch model proved helpful in testing the pro-regenerative activities of small-molecule compounds and observations of peripheral nerve regeneration