**8. Conclusion**

In spite of the neuroprotective properties that characterize resveratrol, it has the drawback of its low bioavailability in the body, so there have been some important efforts to develop

Another example of natural neuroprotective substances is curcumin. It is also a phenolic compound extracted from perennial herb *Curcuma longa* (turmeric), characterized for its antiinflammatory and antioxidant properties [129, 130]. It is mainly known for helping to improve impaired cognitive functions in AD [131]. Among its properties, curcumin inhibits microglial proliferation and differentiation [132] and reduces the inflammation inhibiting amyloid-betainduced expression of specific proteins in monocyte cells, decreasing the transcription of

In transgenic AD mice tg2576, curcumin significantly reduced the levels of amyloid-beta and plaque burden in comparison to not treated tg2576 mice [134]. Finally, a preparation with a high bioavailability of curcumin called "*Longvida*" showed significant improvements in working memory and mood after 4 weeks treatment in a randomized, double-blind, placebo-

In ALS, in a motor neuron-like cellular model from TDP-43MUT, curcumin abolished the excitability previously induced by the mutation, through the inhibition of the oxidative stress

In another example, Riluzole [2-amino-6-(trifluoromethoxy) benzothiazole], which is the only approved disease-modifying drug for ALS, exhibited protective skills in different neurodege‐ nerative alterations and disorders. It acts as a sodium channel blocker and protects neurons against glutamatergic toxic effects [137, 138] and its anti-inflammatory effects have been demonstrated. In ALS, Riluzole prevents hyperexcitability and motor neuron death in ventral spinal cord cell culture [82], it prolongs survival and delays muscle strength deterioration in a mice model of motor neuropathy (similar motor symptoms to ALS) [139], and it preserves motor neuron function in a transgenic model of ALS [140] but just extends the lifespan by a

In AD, due to a previous work indicating that the amyloid-beta peptide significantly alters the expression of glutamatergic transporter (GLUT1), which leads to increase of synaptic gluta‐ mate levels [142], it has been proposed that Riluzole could have potential benefits in the treatment of the disease. Nowadays, there is a phase 2 clinical trial in curse to test cognitive

In PD, Riluzole has shown neuroprotective properties reducing GFAP levels in the lesioned

At this point there is an important body of evidence that supports that neuroimmunomodu‐ lation/neuroinflammation has an active and potent role in many neurodegenerative diseases. Our three examples (AD, PD and ALS) show that instead of having different and specific targets, all of them share common pathways and participants that lead to activation of

microglia and release of inflammatory factors that contribute to neuron death.

analogs with better bioavailability [121].

32 Update on Dementia

inflammatory cytokines, among others [133].

and mitochondrial dysfunction [136].

couple of months in patients [141].

striatum in a rodent model [144].

functional changes in mild AD patients [143].

controlled in a cohort of healthy, elderly subjects [135].

The increase in life expectancy and the associated increase in the elderly population have led to a rise in cases of age-associated diseases; thus neurodegenerative diseases, such as AD, ALS and PD, are transformed into global issues and hot points for research and development of new drugs, especially considering the lack of effective treatment. In fact, most of the currently existing treatments, which are designed on the basis of symptom control, are only palliative.

In this chapter, we have delivered some of the evidence linking the development of inflam‐ matory responses in the central nervous system with neuroinflammatory processes, present in the three very characteristic neurodegenerative conditions such as AD, PD and ALS. As we have mentioned an approach that considers similarities in pathophysiologic aspects of these diseases in spite of the very different clinical spectrum of each of them. This integrative approach is a new alternative road to the study of these diseases. Thus, the elements that define prolonged neuroinflammatory processes in time could be important elements to be considered in the early stage and even during pre-clinical asymptomatic stages of disease. In this context,

**Figure 1.** Model of neuroinflammation and neurodegeneration cycle. The microglial cell at rest is sensitive to different factors or signs of damage that lead to its activation. When these damage signals are maintained in time, the result is an altered response of activated microglial cells. This means that there will be a constant release of cytotoxic factors (mainly proinflammatory cytokines and ROS) that promote neuronal damage and/or lead to neurodegenerative proc‐ esses. Hippocampal neurons, motor neurons, and dopaminergic neurons are susceptible to the action of overactive mi‐ croglia, favoring neurodegeneration, which will trigger or will promote the development of AD, ALS and PD, respectively. In this model, once neurons degenerate, they release substances into the extra-cellular environment that are recognized by the microglia and act as a further sign of damage, promoting a neurodegenerative cycle.

the neuroimmunomodulation hypothesis [48, 58, 145–147] appears as a very plausible explanation for neurodegenerative stereotypical pathogenic process as well as a guide in the search for new therapeutic and new effective disease-modifying treatments.

We have also shown that microglial cell has an important role in the neuroinflammation and how this cell is linked with the neurodegenerative processes in these three diseases (**Fig‐ ure 1**). That is, alterations in hippocampal neurons in AD, in motor neurons in ALS, and in dopaminergic neurons of substantia nigra in the PD are linked directly to the inflammatory response of the surrounding altered microglial cells, promoting the neurodegenerative process.

Another evidence of the effect and the importance of this negative neuroinflammatoryneurodegenerative cycle in the development of these diseases is the experimental response obtained after using compounds with anti-inflammatory properties in AD and ALS [131, 136], turning scientific interest in the development of future treatments that act on abnormal inflammatory response of microglial cell, so that might disrupt the neurodegenerative cycle.

Finally, it is of great interest to search for compounds that have fewer adverse effects and at the same time have a preventive action. In this context, the finding of anti-inflammatory and antioxidant properties in natural compounds opens new research possibilities, projecting a possible neuroprotective and anti-neuroinflammatory effects, which based on control of key elements of neuroimmunomodulation hypothesis could be a new tool for the treatment of these diseases.
