Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats

Abstract

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress.

An Updated Review on Nelumbo Nucifera Gaertn: Chemical Composition, Nutritional Value and Pharmacological Activities

“…Pronuciferine, oleracein-E, ferulic acid and betulinic acid are phytochemicals of lotus that give neuroprotective effects by inhibiting the degradation of nerve fibres. [48][49][50][51] Furthermore, the signalling pathways p38 mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase-3 (MKK3) and bioactive nitric oxide, prostaglandins, and cytokines are responsible for inflammation. Nuciferine is an active chemical constituent in plants that inhibit the signalling pathways and possess anti-inflammatory activity.…”

“…An alternative neurological disorder can occur because of the degradation of nerve fibres. Pronuciferine, oleracein‐E, ferulic acid and betulinic acid are phytochemicals of lotus that give neuroprotective effects by inhibiting the degradation of nerve fibres [48–51] . Furthermore, the signalling pathways p38 mitogen‐activated protein kinase (MAPK), mitogen‐activated protein kinase‐3 (MKK3) and bioactive nitric oxide, prostaglandins, and cytokines are responsible for inflammation.…”

Neuroprotection with Bioactive Compounds

“…Another study focused on neurovascular disease using a haemorrhage-induced brain damage model in rat pups. Treatment of immature rats with betulinic acid hydroxamate, a triterpenoid derivative designed to improve its pharmacological performance, improved motor and cognitive impairment and reduced long-term white matter injury by reducing oxidative stress, inflammation and excitotoxicity [12].…”