**Acknowledgements**

loss of cytoskeletal integrity, TH levels decreased and activation of apoptotic process in dopa-

Other authors demonstrated atrophy and progressive death of dopaminergic neurons dependent on translocation to the nucleus of the inducing factor of Apoptosis-inducing factor (AIF), in which there was no activation of caspase-3 or release of cytochrome C or signs of apoptosis. These researchers further demonstrate that death induced by 6-OHDA in dopaminergic neurons is mediated by activation of AIF-dependent Bax [97]. In this work, AIF activation suggests the involvement of regulated necrosis. The controversy between dependent or independent death of caspase-3 could be explained by the dose, study model and site of injury employed. However, since most evidence includes the involvement of caspase-3 in the 6-OHDA-induced apoptotic process, studies that contradict this fact suggest that 6-OHDA could also lead to neuronal death by apoptosis (independent of caspase-3) or other cell death

All the toxin-induced PD models had scant attention when it comes to the neuroprotective or regenerative strategies. Neuropathology and studies related to the correlation between inflammation and immune cells need to pay much more attention. It is of great interest to know the stimulus by which glial cells respond to the microenvironment and how do they decide whether to release neuroprotective or apoptotic mediators. It would be of interest to know if all the activated glial cells arise from a limited number of precursor cells or if all glia have equal potential to proliferate. It is also most important to study in detail about the types of receptors which are present on glial cells that play a major role in the field of neuroinflammation.

The 6-OHDA injury model has been used to demonstrate the benefits of neurotrophic therapy (NT) [102]. NT consists of directed delivery of genes encoding neurotrophic factors such as brain derived neurotrophic factor (BDNF) [103], glial cell line-derived neurotrophic factor (GDNF) [104–109], cerebral dopamine neurotrophic factor (CDNF) [76, 110], mesencephalic astrocyte-derived neurotrophic factor (MANF) [111], vascular endothelial growth factor (VEGF) [112] through nanoparticles [113, 114], or through viral or non-viral gene vectors [76, 104–107, 115]. The purpose of NT assessed in the 6-OHDA model is to prevent the progression of neurodegeneration and to stimulate the functional regeneration of the nigrostriatal system [116, 117]. The recovery of dopaminergic populations could improve motor function. It is therefore important to identify further underlying mechanisms of oxidative stress, neuroinflammation, neurodegeneration and neuronal death caused by 6-OHDA. This knowledge is

The 6-OHDA model reproduces several cellular processes identified in the PD, therefore it is a key model to explore the molecular bases of cytotoxicity, as well as to study the cellular

minergic neurons of SNpc [51, 85, 92].

382 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

processes (necrosis and autophagy) *in vivo*.

**7. Relevance of 6-OHDA model in gene therapy**

the key to discovery novel therapies to treat PD.

**8. Conclusion**

This work was supported by Consejo Nacional de Ciencia y Tecnología (Cátedra CONACyT # 1840 for DHB) and the Instituto de Neuroetología from Universidad Veracruzana (DGI-174332015137 to MJRH). Special thanks to Nancy Gabriela Vazquez Ixtepan, Cesar Augusto Sandoval Vargas and Erick Hernandez Baltazar for the illustration resources.
