The
receptor binding domain (RBD) of SARS-CoV-2 is the primary
target of neutralizing antibodies. We designed a trimeric, highly
thermotolerant glycan engineered RBD by fusion to a heterologous,
poorly immunogenic disulfide linked trimerization domain derived from
cartilage matrix protein. The protein expressed at a yield of ∼80–100
mg/L in transiently transfected Expi293 cells, as well as CHO and
HEK293 stable cell lines and formed homogeneous disulfide-linked trimers.
When lyophilized, these possessed remarkable functional stability
to transient thermal stress of up to 100 °C and were stable to
long-term storage of over 4 weeks at 37 °C unlike an alternative
RBD-trimer with a different trimerization domain. Two intramuscular
immunizations with a human-compatible SWE adjuvanted formulation elicited
antibodies with pseudoviral neutralizing titers in guinea pigs and
mice that were 25–250 fold higher than corresponding values
in human convalescent sera. Against the beta (B.1.351) variant of
concern (VOC), pseudoviral neutralization titers for RBD trimer were
∼3-fold lower than against wildtype B.1 virus. RBD was also
displayed on a designed ferritin-like Msdps2 nanoparticle. This showed
decreased yield and immunogenicity relative to trimeric RBD. Replicative
virus neutralization assays using mouse sera demonstrated that antibodies
induced by the trimers neutralized all four VOC to date, namely B.1.1.7,
B.1.351, P.1, and B.1.617.2 without significant differences. Trimeric
RBD immunized hamsters were protected from viral challenge. The excellent
immunogenicity, thermotolerance, and high yield of these immunogens
suggest that they are a promising modality to combat COVID-19, including
all SARS-CoV-2 VOC to date.
Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24h and 48h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer.
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