Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice

Abstract

Background Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus partly accounts for the diminished therapeutic discovery. Recent evidence suggests that chondroitin sulphate proteoglycans (CSPG), which can bind to the neural transmembrane protein tyrosine phosphatase-sigma (PTPσ), may facilitate axonal regrowth and remyelination by ameliorating neuroinflammation. Methods A clinically relevant ICH model was established using adult C57BL/6 mice. The mice were then treated systemically with intracellular sigma peptide (ISP), which specifically targets PTPσ. Sensorimotor function was assessed by various behavioral tests and electrophysiological assessment. Western blot was used to verify the expression levels of Iba-1 and different inflammatory cytokines. The morphology of white matter tracts of brain and spinal cord was evaluated by immunofluorescence staining and transmission electron microscopy (TEM). Adeno-associated virus (AAV) 2/9 injection was used to assess the ipsilateral axonal compensation after injury. Parallel in vitro studies on the effects of CSPG interference on oligodendrocyte–DRG neuron co-culture explored the molecular mechanism through which ISP treatment promoted myelination capability. Results ISP, by targeting PTPσ, improved WM integrity and sensorimotor recovery via immunomodulation. In addition, ISP administration significantly decreased WM injury in the peri-hematomal region as well as cervical spinal cord, enhanced axonal myelination and facilitated neurological restoration, including electrophysiologically assessed sensorimotor functions. Parallel in vitro studies showed that inhibition of PTPσ by ISP fosters myelination by modulating the Erk/CREB signaling pathway. Conclusions Our findings revealed for the first time that manipulation of PTPσ signaling by ISP can promote prolonged neurological recovery by restoration of the integrity of neural circuits in the CNS through modulation of Erk/CREB signaling pathway.

Recovery of forearm and fine digit function after chronic spinal cord injury by simultaneous blockade of inhibitory matrix CSPG production and the receptor PTPσ

“…Similarly, ISP has some therapeutic effects after acute T8 cord hemisection in the adult rat when assessed by an automated gait analyses system (Ham et al, 2019, 2020). ISP has also now been shown to be effective in promoting regeneration and functional recovery after SCI when delivered via a plasma exosome based biological scaffold (Ran et al, 2022) as well as a self-assembling peptide hydrogel (Sun et al, 2023) The regenerative potential of blocking the PTPs receptor by ISP has, in addition, been demonstrated in models of MS (Luo et al, 2018), ischemic and hemorrhagic stroke (Luo et al, 2022; Yao et al, 2022), ischemic heart attack (Gardner et al, 2015; Sepe et al, 2022), and peripheral nerve injury (Li et al, 2015; Lv & Wu, 2021). The high dose of 500 ug/day of ISP is that which we chose to use and was effective in our chronic study.…”

Chondroprotectors as modulators of neuroinflammation

“…4) и сенсомоторное восстановление посредством иммуномодуляции (включая электрофизиологически оцениваемые сенсомоторные функции) в модели внутримозгового кровоизлияния (ВК). Ингибирование RPTPσ способствует миелинизации путем модулирования сигнального пути Erk/CREB [16]. ХС способствует формированию эндогенных «ниш» в ПНС, повышающих выживаемость нейронов после травматических повреждений мозга.…”

“…нейропсихиатрия, психосоматика. 2023;15(1):[110][111][112][113][114][115][116][117][118] 113 Ингибирование RPTPσ способствует благоприятным воспалительным реакциям (по данным[16]). а -слева: белок экстрагировали из ткани, окружающей ВМК, показанную белым кругом.…”

“…ПЛ -плацебо (физиологический раствор) Fig. Inhibition of RPTPσ by ISP improves the state of the white matter of the brain and cervical spinal cord in the long term after IH (according to[16]). On the left: representative serial coronal sections of the brain in mice, who received ISP, showing the significantly less volume of red-tinted hematoma than in mice treated with placebo.…”

A dispensable role of oligodendrocyte-derived laminin-α5 in brain homeostasis and intracerebral hemorrhage

“…[2][3][4][5][6][7] In addition, mounting studies report white matter injury and oligodendrocyte (OL) damage after ICH. [8][9][10] OLs are the only myelinating cells in the CNS. They are differentiated from oligodendrocyte precursor cells (OPCs), which are highly proliferative in adult brains.…”