BY AUSTIN LAM
BDNF: In charge of modulation and mediation of neuroinflammation
BDNF expression can be said to have a bi-directional effect on neuroinflammation. By activating its receptor TrkB, its anti-inflammatory effects allow for neuroinflammatory modulation and neuroprotection. An in vitro study found that microglia acutely increased secretion of extracellular BDNF in the context of LPS treatment, which had a negative effect on intracellular BDNF[100]. In activated microglia, BDNF has shown to suppress proinflammatory cytokine release such as that of IL-1β and TNF-α, through inhibition of nitric oxide and NFκB translocation and transcription activity[101] Similarly, BDNF reduces microglial cytotoxicity, protecting cortical neurons by attenuating pro-inflammatory signaling cascades[102]. Interestingly, in aged mice, exogenous BDNF administration dampens microglial density, coupled with decreases in inflammatory cytokine expression in the substantial nigra[103]. Furthermore, the transient secretion of BDNF in microglia may simply be a reactionary response with the goal of alleviating inflammation. This effect may only take place in cases lacking chronicity. Comparing wild-type mice and BDNF +/- mice, BDNF +/- mice appear more susceptible to LPS-induced depressive-like behavior, exhibiting elevated hippocampal IL-1β and TNF-α and microglial activation[98].
The role of BDNF signaling is also region-specific. Agonists of TrkB such as 78- dihydroxyflavone (DHF), and antagonist ANA-12 produce similar antidepressant-like effects in LPS induced depression-like behavior[84]. As for the kynurenine pathway, a lack of BDNF can exacerbate inflammatory effects. IDO increases with peripheral immune activation, diverting tryptophan into production of the neurotoxic metabolites QA and 3-HK. Inflammatory stressors LPS and poly I:C reduce hippocampal BDNF, altering phosphorylation of TrKB, with elevated QA[98]. Therefore, BDNF- TrkB signaling is vital in modulating neuroinflammatory cascades, with its impairment creating vulnerability to development of inflammation-induced depressive phenotypes.
Therapeutic Implications
BDNF-TrkB signalling as a novel therapeutic target contains many challenges, with its potential hindered by neuroanatomical specificity. Although the downregulation of BDNF in the hippocampus and PFC promotes a depression-like phenotype, it is opposed with a paradoxical increase of BDNF levels in the nucleus accumbens (NAc), an important region in the event of anhedonia[104]. In post-mortem studies, cortical regions exhibited decreased BDNF aside from the NAc which showed an increase, confirming this dichotomy[105]. Functionally, regionally selective modulation of TrkB is vital, exemplified by the 7,8-DHF and ANA-12 antidepressant-like effect. TrkB stimulation of the hippocampus, specifically in CA3 and dentate gyrus (DG) of the hippocampus, and TrkB blockade in the NAc would be necessary for therapeutic success.
Systemic administration of BDNF may be out of the question. Its pharmacological unfeasibility is indicated by poor BBB permeability, short half-life, and the potential to induce hyperalgesia during peripheral infusion[106]. Though direct administration presents challenges, TrkB ligands are potential therapeutic antidepressant drugs. A rapid antidepressant effect in the social defeat stress depression model executed by a single administration of TrkB ligands proves promising[104]. However, 7,8-DHF and ANA-12 did not pass the seven-day mark, framing ketamine as a longer-lasting antidepressant. Regardless, ketamine’s influence on greater BDNF expression and TrkB phosphorylation with the absence of excess excitotoxicity suggests a clinically effective. Nasal ketamine, currently approved for treatment-resistant depression, is an exemplar for feasible site-specific delivery.
Alternatively, peripheral inflammatory biomarkers will be useful for identification of inflammation-induced depression. This is heavily limited due to its heavy generalization, considering elevated inflammatory markers are also apparent in bipolar disorder, Parkinson’s disease, and schizophrenia. Overlap in inflammatory profiles of non-depressed individuals further complicates the screening process. Of course, fluctuations of such levels, especially in BDNF, may also be taken into account, yielding inconsistent results.
One emerging approach is the usage of genetically engineered hematopoietic stem cells (HSCs) which can migrate to areas where pathology occurs, expressing neurotrophic factors, although this method will require testing. Another is epigenetic profiling of methylation of BDNF promoters as well as their immune gene variants. This would allow depression treatment to be much more personalized.
Conclusion
BDNF and inflammation are not isolated features of depression, involving the interplay of immune signalling and neurotrophic influence. Boiled down to bi-directional modulation, BDNF expression is downregulated by inflammatory cytokines, leading to inability to regulate immune activity. Understanding this interplay will be especially crucial in inflammationassociated depression and depression vulnerability. Future research targeting BDNF-TrkB signaling, and ross-talk between BDNF and immune pathways will facilitate personalized treatment against the persistence of both depression and neuropsychiatric disorder altogether.
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