Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem^®-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNF_LOW), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNF_HIGH). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNF_HIGH group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNF_HIGH as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer’s disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC₅₀ value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

BACKGROUND: A3-A3 side-to-side bypass is an intracranial-to-intracranial (IC-IC) revascularization option when aneurysm treatment involves occlusion of one anterior cerebral artery (ACA). OBJECTIVE: To describe applications of A3-A3 side-to-side bypass in the management of ACA true and pseudoaneurysms along with a review of pertinent literature. METHODS: Six consecutive patients undergoing an A3-A3 bypass as part of their aneurysm management, representing a single-surgeon experience in a 2-yr period, were included in this retrospective review of a prospectively collected database. RESULTS: Three male and three female patients with a median (range) age of 41.5 (11-69) years representing four ruptured and two unruptured aneurysms were included. Two of the aneurysms were communicating while four were postcommunicating from which three were pseudoaneurysms. Complete aneurysm obliteration was achieved in 5/6 cases. Bypass patency was evaluated in all cases intra- and postoperatively. Good outcomes (modified Rankin Scale score ≤ 2) at follow-up were observed in 4/6 patients. An improvement in mRS scores at the most recent follow-up as compared to preoperative status was achieved in three while scores remained the same in two patients. Ischemic complications related to aneurysm treatment were observed in two patients, both of which achieved good functional recovery upon follow-up. One patient deceased postoperatively due to progression of vasospasm-related infarcts. CONCLUSION: A3-A3 bypass in the management of true as well as pseudoaneurysms of the ACA can achieve good postoperative outcomes in selected patients. Prompt diagnosis and aggressive surgical treatment needs to be pursued if a vessel injury with pseudoaneurysm formation is suspected.