*4.6. Polyunsaturated Fatty Acids*

Another regulator of BDNF seems to be omega-3 polyunsaturated fatty acids (PUFAs). PUFAs are long chains of carbon atoms characterized by a carboxyl group at one end and a methyl group at the other end. As they are unsaturated, they own one or more double bonds between the carbon atoms. Naturally, plant and fish oils, such as flaxseed or salmon have a high content of omega-3 PUFAs [179]. PUFAs play an important role in membrane fluidity, neuronal membranes, neurotransmission, and receptor function [180]. Furthermore, the omega-3 fatty acid, docosahexaenoic acid (DHA), is indispensable for cognition function throughout the lifespan [181]. Indeed, already intrauterine PUFA deficiencies lead to altered cognitive and attentive skills [182].

An animal study showed that omega-3 PUFAs did not only affect the levels of BDNF, but also of glial cell-derived neurotrophic factor (GDNF). The latter is especially important for the recovery of dopaminergic neurons in Parkinson s disease (PD) as it promotes the survival of the dopamine system in the nigrostriatum. Hence, GDNF is shown to be neuroprotective and supporting dopaminergic neurons in PD models, and thus, could potentially be utilized as a therapy against neurodegenerative diseases, especially PD [183,184]. Furthermore, another study found that lower levels of omega-3 fatty acids were associated with lower levels of BDNF in the frontal cortex of rats [185], a part of the brain where various psychiatric illnesses, such as bipolar disease can be manifested [186]. Additionally, omega-3 PUFAs show antimicrobial effects as they increase levels of *Enterobacteria* and *Bifidobacteria*, which both strengthen intestinal permeability, reducing the risk of inflammation [187]. Finally, omega-3 PUFAs have the ability to stimulate macrophages that inhibit the activation of the NLRP3 inflammasome, and thus, decrease levels of the previously mentioned pro-inflammatory IL-1beta [188]. Nevertheless, it is important to note that an excess of omega-6 PUFAs benefits the development of endotoxemia leading to low-grade systematic inflammation, explaining why a low ratio of omega-6/omega-3 PUFAs should be targeted [189,190].

Human studies have discovered a negative correlation between patients with ADHD and levels of PUFAs. An Italian study examined the levels of PUFAs in the blood of 51 ADHD and 22 non-ADHD patients. PUFA levels in the blood of ADHD patients were significantly lower and correlated with behavioral symptoms, but were not associated with cognitive skills [191]. Similarly, a systematic review concluded that in all randomized control trials (RCT) analyzed (7 RCTs, n = 534), omega-3 PUFA supplementation led to an improvement in clinical ADHD symptoms. Furthermore, in three out of the seven RCT s (n = 396), the omega-3 PUFA supplementation was associated with improvements in cognitive skills [192]. Due to these findings, questions of PUFAs being a potential therapeutic medication for ADHD patients seem to be warranted.

Moreover, a double-blind trial [193] assessed the effects of inducing the noradrenaline reuptake inhibitor (Atomoxetine) conventionally used to treat ADHD, to the patient and control group and PUFAs, such as eicosapentanoic acid (EPA) and DHA solely to the ADHD patients. The medication was given on a daily basis for four months to a total of 50 children. Although PUFAs improved ADHD symptoms, this experiment showed no clinically significant difference in the ADHD Conners Parent rating scale, questioning the overall therapeutic effect of PUFAs against ADHD, even if some beneficial effects are evident [193]. Supporting these results, a systematic review discussing results of 14 meta-analyses inducing PUFAs to ADHD children showed a very small effect size when parents and teachers rated children s behavior using the Conners scale [194].

Lastly, on a microbial level, an RCT showed that the intake of PUFAs does not seem to affect the alpha or beta diversity of the microbiota of the participants. Nevertheless, it did show a reversible increase in genera, such as *Bifidobacterium roseburia* and *Lactobaccilus* spp., all of which are important for the production of SCFAs and maintain an anti-inflammatory environment [195]. Similarly, a commentary discussing the importance of long-chain PUFAs as a mean to restore a healthy gut microbiome, deduced that PUFA ingestion may act as a protector from developing systemic inflammation and in the long term, chronic disease. It is, therefore, hypothesized that PUFA supplementation would not only be of therapeutic importance for ADHD, but also a prophylactic measurement against cancer as inflammation leads to immunosuppression and activates immune checkpoints resulting in an optimal tumor microenvironment [196].

Although the collected data show inconclusive results concerning the effect of PUFA supplementation as a therapeutic measurement for ADHD, the indirect effects of ingesting PUFAs and its impact on the microbiome may as well be crucial determinants that could modify the metabolism and consequently the behavioral and cognitive symptoms of ADHD.
