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Page 242 Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02

CONCLUSION
Investigation of inflammatory and neurogenic processes in epilepsy has revealed potential and critical roles
of microglia in several facets of seizure generation. Epilepsy patients take AED with the aim of preventing
seizures, yet studies looking at the anti-inflammatory and neurogenic effects of these drugs are sparse.
Interrogating the literature for effects of AEDs in vivo on microglia, an important modulator of these
processes, result in surprisingly few reports [141-143] .

In vitro studies on microglial cells as mediators of inflammation have demonstrated that topiramate,
a second generation AED, decreased the release of IL-1β, IL-6 and TNF-α [144] . Other AEDs such as
levetiracetam, gabapentin, and phenobarbital showed slight modification in cytokine production [145] .
The first generation AED valproic acid, was shown to increase IL-6 and TNF-α production in LPS-
induced microglial cells [145] , which contrasts with in vivo results where TNF-α and IL-1β were decreased
after valproic acid treatment [143] . It was also demonstrated that the AED levetiracetam suppressed
neuroinflammation and phagocytosis in a pilocarpine induced SE model [143] . Itoh et al. [146] reported that
levetiracetam lessened microglial activation, as demonstrated by lower numbers of Iba-1 positive microglia,
higher ramified shape, and low expression of pro-inflammatory cytokines. While the results of in vitro
studies may eventually be applicable to the clinic, they highlight the need for clarification of the effects of
AEDs on inflammation in vivo.

Studies concerning AEDs and neurogenesis are also extremely limited. Pregabalin, a widely used AED
with an unknown mechanism of action, has been shown to accelerate the maturation of granule cells in the
[148]
dentate gyrus [147] . In rats, lamotrigine increased the number of newborn cells in the hippocampus and
increased neurogenesis [149] . Valproic acid also induced neurogenesis, but these effects were not induced by
phenobarbital and topiramate [149] .

Epileptogenic changes in the brain are provoked by inflammation and increased neurogenic levels post-
seizure. To control this process, a greater understanding of microglial contributions is needed and could
provide a mechanism and target for a new generation of AEDs.

DECLARATIONS
Acknowledgments
We would like to thank members of the Tsirka lab for helpful discussions and feedback. TRV is a recipient
of a National Science Foundation Graduate Research Fellowship.

Authors’ contributions
Co-wrote review article, edited review, generated the images: Victor TR
Co-wrote review article, edited article, correspondence: sirka SE

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was partially supported by the National Science Foundation Graduate Research Fellowship under
grant no. 1315232, and NIH T32GM127253.

Conflicts of interest
All authors declared that there are no conflicts of interest.