Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries.

BACKGROUND: Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area. METHODS: We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries. RESULTS: We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR+ immature neuroblasts in the SVZ. In accordance, the inhibition of the TGF-α receptor, EGFR promotes migration of neuroblasts toward the injury leading to an elevated number of neuroblasts within the perilesional area. CONCLUSIONS: Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.

Migratory Response of Cells in Neurogenic Niches to Neuronal Death: The Onset of Harmonic Repair?

Harmonic mechanisms orchestrate neurogenesis in the healthy brain within specific neurogenic niches, which generate neurons from neural stem cells as a homeostatic mechanism. These newly generated neurons integrate into existing neuronal circuits to participate in different brain tasks. Despite the mechanisms that protect the mammalian brain, this organ is susceptible to many different types of damage that result in the loss of neuronal tissue and therefore in alterations in the functionality of the affected regions. Nevertheless, the mammalian brain has developed mechanisms to respond to these injuries, potentiating its capacity to generate new neurons from neural stem cells and altering the homeostatic processes that occur in neurogenic niches. These alterations may lead to the generation of new neurons within the damaged brain regions. Notwithstanding, the activation of these repair mechanisms, regeneration of neuronal tissue within brain injuries does not naturally occur. In this review, we discuss how the different neurogenic niches respond to different types of brain injuries, focusing on the capacity of the progenitors generated in these niches to migrate to the injured regions and activate repair mechanisms. We conclude that the search for pharmacological drugs that stimulate the migration of newly generated neurons to brain injuries may result in the development of therapies to repair the damaged brain tissue.

Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases.

Neurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems that produce brain damage from which there is no recovery. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear to be similar, suggesting common neurodegenerative pathways. It is well known that oxidative stress and the production of reactive oxygen radicals plays a key role in neuronal cell damage. It has been proposed that this stress, among other mechanisms, could contribute to neuronal degeneration and might be one of the factors triggering the development of these pathologies. Another common feature in most neurodegenerative diseases is neuron hyperexcitability, an aberrant electrical activity. This review, focusing mainly on primary motor cortex pyramidal neurons, critically evaluates the idea that oxidative stress and inflammation may be involved in neurodegeneration via their capacity to increase membrane excitability.

Refinement of Active and Passive Membrane Properties of Layer V Pyramidal Neurons in Rat Primary Motor Cortex During Postnatal Development.

Achieving the distinctive complex behaviors of adult mammals requires the development of a great variety of specialized neural circuits. Although the development of these circuits begins during the embryonic stage, they remain immature at birth, requiring a postnatal maturation process to achieve these complex tasks. Understanding how the neuronal membrane properties and circuits change during development is the first step to understand their transition into efficient ones. Thus, using whole cell patch clamp recordings, we have studied the changes in the electrophysiological properties of layer V pyramidal neurons of the rat primary motor cortex during postnatal development. Among all the parameters studied, only the voltage threshold was established at birth and, although some of the changes occurred mainly during the second postnatal week, other properties such as membrane potential, capacitance, duration of the post-hyperpolarization phase or the maximum firing rate were not defined until the beginning of adulthood. Those modifications lead to a decrease in neuronal excitability and to an increase in the working range in young adult neurons, allowing more sensitive and accurate responses. This maturation process, that involves an increase in neuronal size and changes in ionic conductances, seems to be influenced by the neuronal type and by the task that neurons perform as inferred from the comparison with other pyramidal and motor neuron populations.

Age-Dependent Vulnerability to Oxidative Stress of Postnatal Rat Pyramidal Motor Cortex Neurons.

Oxidative stress is one of the main proposed mechanisms involved in neuronal degeneration. To evaluate the consequences of oxidative stress on motor cortex pyramidal neurons during postnatal development, rats were classified into three groups: Newborn (P2-P7); infantile (P11-P15); and young adult (P20-P40). Oxidative stress was induced by 10 µM of cumene hydroperoxide (CH) application. In newborn rats, using the whole cell patch-clamp technique in brain slices, no significant modifications in membrane excitability were found. In infantile rats, the input resistance increased and rheobase decreased due to the blockage of GABAergic tonic conductance. Lipid peroxidation induced by CH resulted in a noticeable increase in protein-bound 4-hidroxynonenal in homogenates in only infantile and young adult rat slices. Interestingly, homogenates of newborn rat brain slices showed the highest capacity to respond to oxidative stress by dramatically increasing their glutathione and free thiol content. This increase correlated with a time-dependent increase in the glutathione reductase activity, suggesting a greater buffering capacity of newborn rats to resist oxidative stress. Furthermore, pre-treatment of the slices with glutathione monoethyl ester acted as a neuroprotector in pyramidal neurons of infantile rats. We conclude that during maturation, the vulnerability to oxidative stress in rat motor neurons increases with age.