*6.3. Characteristics of the Ocular Motor System after Axotomy*

#### 6.3.1. Regulation of Trophic Factors

Upregulation of VEGF expression seems to be a common phenomenon in response to a lesion since any injury to the CNS is known to trigger a hypoxia process involving VEGF expression [144,174]. These findings suggest that the upregulation of endogenous VEGF may be related to its neuroprotective role, so there would be a selective and preferential induction of this neurotrophic factor in some areas of the brain, which would allow greater binding of the ligand to its receptors and would provide greater trophic support [175]. In this sense, it is important to highlight that extraocular motoneurons suffer an increase in the expression of VEGF and Flk-1 in response to axotomy, an increase that was not observed in facial and hypoglossal motoneurons [151].

That increases in VEGF expression has been previously detected in response to ischemia or seizures in both neurons and glial cells of the hippocampus, thalamus, amygdala, and neocortex [175,176]. These results have great functional relevance since VEGF seems to maintain neuromuscular communication even during the denervation processes of the target and are consistent with the neuroprotective role that VEGF exerts on motoneurons, prolonging their survival and improving motor performance [17,82,177,178].

As discussed before, it is well known that the neuroprotective effects that VEGF plays on motoneurons are mediated by the Flk-1 receptor, which is involved in the release of growth factors [64] and mediates trophic functions [37,38,40]. Therefore, this evidence emphasizes the importance of the increased expression of Flk-1 observed in the ocular motoneurons in response to axotomy [151], this being one of the possible keys to the greater resistance shown by this population against neurodegeneration.

Previous studies showed changes in the expression of other trophic factors, such as neurotrophins, or their receptors in motoneurons after axotomy [120,132,179]. It has also been described that axotomized motoneurons experience a decrease in the expression of the protein acetylcholintransferase (ChAT) [120,132,164]. It is important to note that both the immunoreactivity of ChAT and the activity and mRNA of this enzyme are also markedly reduced in cases of ALS [180–182]. In fact, the motoneurons of the anterior horn of the spinal cord suffer a decrease in ChAT activity from early stages, compared to control neurons [183], which suggests that a reduction in ChAT expression is a specific and initial change in disease pathogenesis [184]. It is worth mentioning that the exogenous administration of VEGF at the site of the injury is capable of preventing the loss of the cholinergic phenotype in the axotomized motoneurons, which allows the ocular motoneurons to retain a neurotransmissive phenotype [164]. These studies emphasize the importance of the neuroprotective effect that VEGF has on motoneurons by maintaining its synaptic transmission capacity.

Therefore, all this evidence suggests that facing an injury to the CNS that involves the loss of the muscular target, the ocular motoneurons are capable of expressing a greater amount of VEGF and Flk-1 in their neuronal somas as a compensatory mechanism to keep them protected and in an operational state [151,164]. In summary, the improvement in endogenous VEGF levels highlights autocrine functions, and upregulation of the Flk-1 receptor emphasizes the paracrine functions of VEGF in its neuroprotective effect against degeneration [152].
