**7. Substances that inhibit microglial activation and neuroinflammation are protective in neurodegenerative diseases**

Many different substances that prevent the triggering of inflammation in neurons have been used against AD, PD and ALS on primary cell cultures, mice models, and humans.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural polyphenolic compound with antioxidant properties capable of penetrating the blood-brain barrier efficiently [118–120].

Regarding AD, it has been shown that resveratrol inhibits amyloid-beta aggregation *in vitro* [121] and that has neuroprotective properties in cell cultures and animal models [122, 123]. Moreover, a recent clinical study showed that resveratrol was safe and well tolerated in individuals with mild to moderate Alzheimer disease, and although some biomarker levels were altered, a larger research to determine whether resveratrol may be beneficial for AD patients is necessary [124].

In murine models of ALS, resveratrol ameliorated motor neuron loss and degeneration, delayed disease symptoms onset, improved locomotion impairment, and extended the lifespan in the SOD1G93A mice [125], and importantly, it was found that resveratrol adminis‐ tration reduces microglial immunoreactivity in the SOD1G93A mice spinal cord [125]. It has been amply described that one of the mechanisms by which resveratrol promotes neuroprotection is increasing Sirt1 activity, whose increase and activation were demonstrated in motor neuron from spinal cord of SOD1G93A mice [125], showing a crucial role of the antioxidant in the prevention of the neuroinflammation in the disease, specifically through the microglial activation and not astroglial activation. This is in concordance with another evidence that showed that despite that resveratrol was capable of preventing slowly the ROS increase, it could not improve motor neuron survival in a rat primary spinal cord culture after exposition to astrocyte conditioned media from transgenic SOD1G93A [126].

In PD resveratrol participation is still being studied, but it seems to have a protective effect against dopamine-induced cytotoxicity and certain toxins and can also attenuate the inflam‐ matory response in activated microglia [127, 128].

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 analogs with better bioavailability [121].

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 inflammatory cytokines, among others [133].

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

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 and mitochondrial dysfunction [136].

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 couple of months in patients [141].

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 functional changes in mild AD patients [143].

In PD, Riluzole has shown neuroprotective properties reducing GFAP levels in the lesioned striatum in a rodent model [144].

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.
