Bacterial meningitis is a severe infection of the central nervous systems (CNS), with an annual occurrence of 0.9 per 100,000 people in developing countries [
1,
2]. The most common causative agent is
Streptococcus pneumoniae, with a case fatality rate of ~30% in developed countries and nearly 50% in less-developed countries [
3‐
5]. Moreover, ~50% of survivors suffer from persistent neurological sequelae throughout their life, including learning and memory deficits, seizures, and hearing impairment [
6,
7]. The inflammatory response plays a vital role in disease pathogenesis, with bacterial compounds recognized by brain-resident immune cells capable of recruiting myeloid differentiation factor 88 (MyD88) and inducing nuclear translocation of nuclear factor kappa B (NF-κB), followed by the production of inflammatory mediators [
8,
9]. This enhanced inflammatory response triggered to eliminate bacterial components exerts both defensive and neurotoxic effects [
10]. Although therapies necessary to reduce inflammation are required, neurological sequelae associated with the disease correlate with hippocampal apoptosis caused by both the bacterial toxins and the intensive immune response [
10]. A single treatment capable of reducing both inflammation and hippocampal apoptosis could potentially improve outcomes in children with
S. pneumoniae meningitis.
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic family, which plays an important role in the development, differentiation, and survival of neurons in the CNS [
11,
12]. BDNF exerts neuroprotective effects in multiple CNS diseases following its high-affinity binding to tropomyosin-receptor kinase B (TrkB) [
13,
14]. In recent years, significant effort has been expended to identify the neuroprotective effects of BDNF on
S. pneumoniae meningitis in both animal experiments and clinical studies. Our previous study reported the levels of BDNF and its receptor TrkB increased following acute
S. pneumoniae meningitis but subsequently declined over time, especially following administration of antibiotics [
15]. Similarly, increased BDNF levels were also observed in the serum and cerebrospinal fluid (CSF) of pediatric patients with CNS infections on the day of admission [
16]. Increased BDNF synthesis during the acute phase of meningitis could stimulate proliferation of dentate granule cells and promote neurogenesis after bacterial meningitis [
17]; however, this self-reparative capacity is insufficient, given that most newly generated cells are unable to differentiate into immature neurons and neurons in experimental
S. pneumoniae meningitis [
9], which worsens as BDNF decreases over time. Additionally, Barichello et al. [
18] reported that decreases in BDNF levels during the long-term phase of meningitis were correlated with behavioral deficits in adult animals submitted to meningitis during the neonatal period. Interestingly, our previous study reported that administration of exogenous BDNF increased rates of neuron survival [
18], and it was recently reported that exogenous BDNF increases neurogenesis of neuron stem cells in the hippocampus after
S. pneumoniae meningitis [
9]. In addition to its neuroprotective effects, BDNF participates in anti-inflammatory and anti-apoptotic processes according to a study of experimental allergic encephalomyelitis [
13]. Furthermore, BDNF can attenuate ischemic-hypoxic injury by modulating local inflammation in rats suffering from ischemic stroke [
19]. Taken together, these findings indicate BDNF involvement in regulating inflammatory processes; however, the mechanisms associated with BDNF signaling related to these responses remain unknown. BDNF-related neuroprotective effects are elicited by activation of extracellular signal-related kinase (ERK)- and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-signaling pathways, and recent evidence suggests that PI3K participates in negative regulation of inflammatory pathways [
13,
20,
21]. However, the contribution of this signaling pathway to BDNF-associated prevention of brain injury related to
S. pneumoniae meningitis remains unclear.
Here, we explored whether BDNF/TrkB interaction modulates localized inflammation in the infected brain by exerting neuroprotective effects through reductions in hippocampal apoptosis associated with S. pneumoniae meningitis. We further investigated whether these effects are mediated by the MyD88/NF-κB- and PI3K/AKT-signaling pathways.